RARE DISEASE
Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality
Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality
Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality
Synonyms: 5q- syndrome
Synonyms: 5q- syndrome
Synonyms: 5q- syndrome
Drug discovery
5
drugs
With orphan designations
Overview
Myelodysplastic syndrome with isolated del(5q) is a WHO-defined subtype characterized by an interstitial deletion in chromosome 5q31-q33, often presenting as macrocytic anemia with normal/elevated platelets and bone marrow megakaryocytic dysplasia [1][5][6]. It primarily affects elderly women and generally follows an indolent course, though TP53 mutations increase leukemia transformation risk and reduce lenalidomide responsiveness [6][7][18]. Lenalidomide remains first-line therapy for transfusion-dependent anemia, achieving transfusion independence in ~70% of patients [3][8][13].
Therapies
First-line: Lenalidomide (67% transfusion independence rate, median 2-year response) [3][8][18]
TP53-mutated cases: Consider hypomethylating agents or allogeneic transplant due to accelerated progression [3][18][19]
Refractory cases: Combination therapies or clinical trials targeting PP2A pathway [8][13][16]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
274 drug discovery papers about Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
274 drug discovery papers about Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-04-17 | Co-occurrence of High-Risk Myelodysplastic Syndrome With a Complex Karyotype/TP53 Mutation and IgG Lambda Monoclonal Gammopathy of Undetermined Significance
Myelodysplastic syndrome (MDS) represents a group of hematologic disorders marked by abnormal cellular development in the bone marrow, while monoclonal gammopathy of undetermined significance (MGUS) involves abnormal plasma cells without symptomatic manifestations. This paper presents a compelling case of a 74-year-old Hispanic female diagnosed with a rare combination of high-risk MDS characterized by a complex karyotype and TP53 mutation, alongside IgG lambda MGUS. The patient's clinical presentation included a spectrum of symptoms such as body aches, rash, fever, dyspnea, and bloody watery diarrhea. Initial diagnostic evaluations yielded no significant findings, but subsequent investigations revealed abnormalities in both bone marrow and peripheral blood, indicative of coexisting MDS and MGUS. Chromosomal analysis further confirmed the presence of a complex karyotype with multiple aberrations, notably including 5q deletion. This case underscores the rarity of simultaneous high-risk MDS and MGUS, particularly with the additional complexity of a TP53 mutation and complex karyotype. It underscores the imperative for continued research efforts to elucidate the underlying mechanisms and optimal management strategies for such intricate cases. Moreover, it highlights the therapeutic challenges posed by concurrent MDS and plasma cell disorders, advocating for more aggressive interventions such as stem cell transplantation as potential avenues for improved patient outcomes.
2024-03-21 | Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.
Abstract A remarkably high rate of post‐transplant relapse in patients with TP53‐mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT ( N = 38) versus non‐HSCT ( N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non‐HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion ( p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non‐HSCT) had multi‐hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non‐HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow‐up was 15.1 months for HSCT and 5.7 months for non‐HSCT. Median disease‐free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non‐HSCT cohorts, respectively. Non‐relapse mortality at 12 months was 22% versus 44% for HSCT versus non‐HSCT. In the HSCT cohort, the rate of grade II–IV acute and chronic graft‐versus‐host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non‐HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53‐mutated MDS/AML remain an area of unmet clinical need.
2018-03-01 | Allogeneic Stem Cell Transplantation for Myelodysplastic Syndrome Patients with a 5q Deletion
Abstract
The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P < .001), whereas female recipient sex resulted in improved survival (hazard ratio, .61; 95% CI, .41 to .90; P = .01). We conclude that allogeneic HCT can cure a subset of patients with MDS and a del (5q) abnormality.
2014-02-10 | Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.
2009-02-24 | Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). However, the morbidity and mortality associated with conventional HSCT have traditionally prevented many patients from undergoing such treatment. Recent advances, including better prognostic algorithms, the introduction of reduced intensity conditioning regimens, and experience with alternative donors, have made HSCT a realistic option for an increasing number of patients with MDS.
proteins
2024-03-30 | Luspatercept in low-risk myelodysplastic syndromes: a paradigm shift in treatment strategies
In patients with myelodysplastic syndromes (MDS), anemia is prevalent affecting 80%-85% of low-risk (LR-MDS) patients, with 40% eventually requiring red blood cell (RBC) transfusions. Except forlenalidomide, exclusively approved for those with deletion of chromosome 5q,erythropoiesis-stimulating agents (ESAs) are the primary treatment choice for low-risk patients. Those unresponsive to ESAs face limited alternatives, eventually necessitating long-term RBC transfusions, leading to secondary iron overload and adversely affecting quality of life (QoL). Luspatercept is a pioneering erythroid maturation agent. It received approval by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for treating adults experiencing transfusion-dependent anemia associated with LR-MDS or β-thalassemia. Recently, the FDA approved luspatercept as first- line therapy in patients with very low- to intermediate-risk MDS who require RBC transfusions and have not previously received ESAs. This review summarizes the historical impact of luspatercept intreating LR-MDS unresponsive to ESAs and illustrates its potential benefit asfrontline therapy in MDS and its employment in patients with myelofibrosis-induced anemia. Luspatercept has revolutionized the therapeutic paradigm of LR-MDS, for which there was a limited therapeutic arsenal, especially in the setting of patients who did not respond or fail after ESA treatment.
2023-11-01 | [Recent findings in myelodysplastic syndrome].
Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myeloid leukemia (AML).Recent developments include the classification and the estimation of prognosis. In 2022 the former 2016 WHO classification was replaced by the ICC and WHO 2022 classification. Both classifications have included precursor lesions (CHIP and ICUS), both distinguish between three molecularly cytogenetically defined subgroups - del(5q), TP53, SF3B1 - and morphologically defined subgroups with differences in blast threshold (WHO: 20%; ICC: 10%) for the differentiation from AML. However, although prognostic factors influenced the classification-subgroups, it is important to distinguish the prognosis, which is crucial for optimal therapeutic decision making. Since 2022, the IPSS-M has been available for this purpose, which represents an expansion of the well-established IPSS-R. It could improve prognosis estimation by adding molecular data, recently this could have been confirmed in real world cohorts. The IPSS-M also represents an important extension with regard to prognosis estimation for patients with therapy-related MDS.In 2020 Luspatercept has been approved for transfusion-dependent lower risk MDS patients harboring ring sideroblasts ± an SF3B1 mutation after failure of an erythropoiesis stimulating agent. The COMMANDS trial has just reported an interim analysis, where the superiority of luspatercept in the 1st line compared to erythropoietin could be demonstrated. In addition, data from the phase III trial with Imeltelstat give reason to hope that we will be able to offer a new second-line therapy to LR-MDS patients. For higher risk MDS patients azacitidine therapy remains the standard of care, results of phase III trials of combination therapies must be awaited.NEUERUNGEN – KLASSIFIKATION UND PROGNOSE: Die WHO-2016-Klassifikation wurde durch die ICC und die Klassifikation der WHO 2022 abgelöst. Die beiden Klassifikationen weisen viele Ähnlichkeiten auf; den größten Unterschied stellt der Blastengrenzwert dar. Seit 2022 steht der IPSS-M, der molekulare Aberrationen berücksichtigt, zur Verfügung und verbessert im Vergleich zum IPSS-R die Prognosegenauigkeit für das progressionsfreie Überleben und das Gesamtüberleben. Somit soll eine optimierte therapeutische Entscheidungsfindung ermöglicht werden. NEUERUNGEN – THERAPIE: 2020 wurde Luspatercept für transfusionsabhängige Patient*innen mit Ringsideroblasten ± einer SF3B1-Mutation zugelassen. Rezent konnte die Überlegenheit von Luspatercept in der ersten Linie gegenüber EPO gezeigt werden. Mit Imetelstat können wir in Zukunft ggf. eine neue Zweitlinientherapie für LR-MDS-Patient*innen nach Versagen von EPO anbieten. Für High-Risk-Patient*innen ist die Therapie mit Azacitidin weiterhin der Therapiestandard – die Ergebnisse der Phase-III-Studien der Kombinationstherapien müssen abgewartet werden.
2023-07-03 | Why do we not have more drugs approved for MDS? A critical viewpoint on novel drug development in MDS.
Approval of new agents to treat higher risk (HR) myelodysplastic syndrome (MDS) has stalled since the approval of DNA methyltransferase inhibitors (DNMTi). In addition, the options for patients with lower risk (LR) MDS who have high transfusion needs and do not harbor ring sideroblasts or 5q- syndrome are limited. Here, we review the current treatment landscape in MDS and identify areas of unmet need, such as treatment after failure of erythropoiesis-stimulating agents or DNMTis, TP53-mutated disease, and MDS with potentially targetable mutations. We discuss how our understanding of MDS pathogenesis can inform therapy development, including treating HR-MDS similarly to AML and pursuing therapies to address splicing factor mutations and dysregulated inflammation. We then bring a critical lens to current methodology of MDS studies and propose solutions to improve the efficiency and yield of these clinical trials, including using the most meaningful response metrics and expanding enrollment.
2019-07-05 | [Treatment for low-risk myelodysplastic syndromes].
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenia and leukemic transformation. Allogeneic hematopoietic stem cell transplantation is the only potential curative therapy for MDS; however, the first treatment option for transfusion-independent patients with low-risk MDS remains limited. Recently, lenalidomide has become available for patients with low-risk MDS and symptomatic anemia with del (5q) (5q-syndrome), darbepoetin (DA) for those with anemia without del (5q), and azacitidine for those with DA-resistant anemia or anemia with thrombocytopenia. DA may be the first treatment option for anemic patients with low-risk MDS because the incidence of 5q-syndrome is rare in Japan in contrast to western countries. It has been reported that primary or secondary failure of Erythropoiesis-stimulating agents (ESA) correlated with a higher risk of acute myeloid leukemia, and none of the leading second-line treatments significantly improved survival. In this review, I have described the treatment strategies in using such drugs and future perspectives for low-risk MDS.
2016-12-07 | Erythropoiesis‐stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower‐risk myelodysplastic syndrome
Abstract Background The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower‐risk myelodysplastic syndrome ( MDS ) from 17 European countries from both university hospitals and smaller regional hospitals. Objective The aim of this study was to describe the usage and clinical impact of erythropoiesis‐stimulating agents ( ESA s) in 1696 patients enrolled between 2008 and 2014. Methods The effects of ESA s on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. Results ESA treatment (median duration of 27.5 months, range 0–77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit ( HR 0.82, 95% CI: 0.65–1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions ( P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post‐ ESA treatment transfusion was 6.1 months (IQR: 4.3–15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0–47.8 months) in patients without prior transfusions ( HR 2.4, 95% CI: 1.7–3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death ( HR 0.65, 95% CI: 0.45–0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia ( HR 0.71, 95% CI: 0.39–1.29, P = 0.27). Conclusion Appropriate use of ESA s can significantly delay the onset of a regular transfusion need in patients with lower‐risk MDS .
small molecules
2026-08-20 | Isolated del(5q) with myeloproliferative driver mutations: A systematic review of published cases and clinical implications.
Myeloid neoplasms harboring both an isolated deletion of chromosome 5q (del(5q)) and myeloproliferative neoplasm (MPN) driver mutations (JAK2, CALR, MPL) constitute a rare and diagnostically challenging subset, often described with features overlapping those of myelodysplastic syndromes (MDS) and MPN. We systematically reviewed published case reports and case series of adult patients with myeloid neoplasms and concomitant isolated del(5q) and MPN driver mutations. A comprehensive search of PubMed and Google Scholar from inception through 31 December 2024 was performed using terms related to "del(5q)", "JAK2", "CALR", "MPL", and "myeloid neoplasm". Eligible reports required documentation of isolated del(5q) and at least one MPN driver mutation with extractable clinical, cytogenetic, and/or molecular data. Data were synthesised descriptively; no quantitative meta-analysis was feasible. The review followed PRISMA 2020 guidelines and was registered post-study at INPLASY2025120046. Twenty publications reporting 24 patients (diagnosed between 2006 and 2021) met the inclusion criteria. The median age was 70.5 years with a female predominance. Most patients presented with macrocytic anemia, thrombocytosis, and megakaryocytic dysplasia, frequently accompanied by marrow fibrosis. JAK2 V617F was the predominant mutation, whereas CALR and MPL were rarely described. Lenalidomide achieved hematologic responses in 14 of 17 evaluable patients and cytogenetic responses in 8 of 16; JAK2 V617F clearance occurred in 4 of 13. During a median follow-up of approximately two years, 5 of 24 patients progressed to acute myeloid leukemia. Reported cases with isolated del(5q) and an MPN driver mutation suggest a rare overlap presentation with mixed dysplastic and proliferative features. Lenalidomide appears to provide hematologic and cytogenetic benefit in some patients, although molecular persistence and progression to AML have been observed. Given the limited number and heterogeneity of published cases, these observations should be interpreted with caution. Larger, systematically collected datasets are needed to better understand the clinical significance and optimal management of this combination.
2026-08-19 | ALK-fusion-positive non-small cell lung cancer concomitant with 5q deletion myelodysplastic syndrome: a case report
Multiple primary malignant neoplasms (MPMNs) refers to the concurrent or sequential development of at least two distinct primary malignant tumors within the body, arising from the same organ or different organs. The current manuscript discusses the unique clinical case of a female patient diagnosed with concomitant metastatic ALK-positive NSCLC and del 5q-MDS and was treated for both entities with oral systemic treatments only with a remarkable response for both diseases.
2026-06-17 | The role of adding a hormonal component to the pathogenetic therapy of myelodysplastic syndrome
Background. In myelodysplastic syndrome (MDS), an imbalance of interleukins causes increased apoptosis of hematopoietic stem cells, i.e. cytopenia. Activation of inflammasomes due to specific mutations, for example, SF3B1 or del(5q), is associated with different cytokine profiles and inflammatory phenotypes. Objective: to study the levels of pro-inflammatory and anti-inflammatory interleukins against the background of adjuvant hormonal therapy in patients with MDS. Materials and methods. Three clinical observation groups were formed, in which patients were assigned the appropriate treatment: lenalidomide according to the monotherapy regimen (L group), lenalidomide and dexamethasone p/o tablet 3 mg per day in the first month and 1 mg in the next 2 months (LD group), as well as lenalidomide and prednisolone p/o tablet 15 mg per day in the first month and 10 mg in the next 2 months (LP group). Before and after treatment (in 3 months), the levels of pro-inflammatory and anti-inflammatory cytokines were assessed. Results. The effectiveness of adjuvant hormonal anti-inflammatory therapy in patients with MDS receiving treatment with lenalidomide was established. A decrease in proinflammatory IL-6 levels from 9.2 ± 1.1 to 6.7 ± 0.8 pg/ml in participants receiving dexamethasone, and from 8.8 ± 1.3 to 4.9 ± 1.8 pg/ml in those receiving prednisone indicates the benefit of using hormonal drugs to reduce systemic inflammation in MDS. No less significant for clinical practice was a decrease demonstrated by IL-1β in the group receiving prednisone together with lenalidomide: from 12.8 ± 2.0 to 5.8 ± 1.3 pg/ml, the result is significant compared to the indicators before treatment, as well as to the L group, p < 0.05. At the same time, an important result was an increase in the level of anti-inflammatory interleukins: IL-4 against the background of taking prednisolone and IL-10 in the group of patients who were prescribed dexamethasone. Conclusions. The prescription of hormonal adjuvant therapy led to a decrease in the levels of pro-inflammatory interleukins and an increase in anti-inflammatory ones. At the same time, in the group of patients who took only lenalidomide without hormones, the concentration of TNF-α in serum increased from 8.4 ± 2.0 to 12.2 ± 2.2 pg/ml. Research on the effectiveness of adjuvant protocols in the comprehensive treatment of MDS must be continued, because any therapeutic intervention that reduces the intensity of systemic inflammation and can potentially improve the quality of life of patients and the prognosis of the disease justifiably deserves the attention of scientists and clinicians
2026-06-01 | Mutational dynamics in patients with del(5q) MDS treated with lenalidomide prior to transfusion dependency—Molecular results from the Sintrarev clinical trial
Abstract Lenalidomide (Len) is the standard of care for red blood cell transfusion‐dependent (TD) patients with myelodysplastic syndromes (MDS) and del(5q). A Phase III clinical trial (SintraRev) demonstrated better efficacy of early treatment with Len in anemic del(5q) MDS patients prior to TD, but clonal evolution with this approach remained unexplored. We evaluated changes in mutational profiles of non‐TD del(5q) MDS patients treated with Len to assess whether early administration of Len could reduce or worsen the mutational burden in those patients. The molecular profile of patients included in the SintraRev trial was analyzed by targeted sequencing. Median follow up of patients was 60.6 months (interquartile range [IQR] 32.3–73.9). Next‐generation sequencing (NGS) was available in a total of 51 patients. SF3B1 (25.5%) and TP53 (21.3%) were the most frequently mutated genes. Clonal evolution during treatment among patients receiving Len or placebo (Pcb) was markedly different, with a 41.2% reduction in predominating clones in the Len arm, while remaining stable/increase in 100% of Pcb patients after 2 years. Mutations in SF3B1 and TP53 decreased/remained stable in the Len cohort, while only DNMT3A mutations increased under cytogenetic response. Regarding disease progression, only 20% of Len patients carrying TP53 mutations developed acute myeloid leukemia (AML), similar to the Pcb group (20%). Treatment with low‐dose Len in transfusion‐independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53 ‐mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.
2026-04-07 | Association between treatment-emergent cytopenias and clinical responses to imetelstat in lower-risk myelodysplastic syndromes
Myelodysplastic syndromes/neoplasms (MDS) are myeloid malignancies with ineffective hematopoiesis, resulting in variable cytopenias and increased risk of progression to acute myeloid leukemia (AML) [ 1 , 2 ]. Imetelstat, a first-in-class competitive telomerase inhibitor, is an approved therapy in the US and Europe for adults with lower-risk MDS (LR-MDS) with red blood cell (RBC) transfusion-dependent (TD) anemia who are relapsed or refractory to, or ineligible for, erythropoiesis-stimulating agents (ESAs) [ 3 , 4 ]. In the Phase III IMerge trial (NCT02598661), a significantly higher proportion of patients on imetelstat achieved RBC transfusion independence (TI) than placebo [ 5 ]. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (68%) and thrombocytopenia (62%), mostly occurring within the first 3 cycles of imetelstat [ 5 ]. These events were generally transient and associated with similarly low rates of grade 3/4 clinical consequences (bleeding, infection, and febrile neutropenia) as placebo [ 5 ]. As neutropenia and thrombocytopenia occurring early with lenalidomide treatment have been correlated with clinical response in patients with del(5q) LR-MDS, suggesting an on-target, disease-modifying effect on the del(5q) clone [ 6 ], we conducted a post hoc analysis to evaluate the association between early treatment-emergent cytopenias with imetelstat and clinical responses.
oligonucleotides
2022-02-28 | Effect of miR-223-3p on cell pyroptosis in myelodysplastic syndrome and its mechanism via regulating the expression of NLRP3
This study aimed to investigate the regulatory mechanism of the miR-223-3p/NLRP3 signaling axis in the progression of myelodysplastic syndrome (MDS). For this purpose, SKM-1 cells were transfected and three groups were set up according to different transfection protocols: si-NC group (NLRP3 silencing negative control plasmid), si-NLRP3 group (NLRP3 silencing plasmid), miR-223-3p mimic- NC group (miR-223-3p overexpressing negative control plasmid), miR-223-3p mimic group (miR-223- 3p overexpressing plasmid), miR-223-3p mimic+oe-NLRP3 group and miR-223-3p mimic+oe-NLRP3 group (NLRP3 silencing combined with miR-223-3p overexpressing plasmid). Normal bone marrow cells were used as the control. qRT-PCR was used to detect relative expressions of NLRP3 and miR- 223-3p; and Western blot to detect Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9 expressions. Cell proliferation detection used CCK-8 assay, cell cycle distribution detection adopted flow cytometry, and cell migration and invasion analyses relied on Transwell assay. Dual-luciferase reporter assay verified the relationship between NLRP3 and miR-223-3p. An animal experiment was finally conducted to confirm the results obtained in cells. Results showed that compared with normal bone marrow cells and K562 cells, there were significantly upregulated NLRP3 expression and upregulated expression of miR-223-3p in SKM-1 cells (all P<0.05). Compared with the si-NC group and mimic-NC group respectively, the si-NLRP3 group and miR-223-3p mimic group showed inhibited proliferation, blocked cells in the G0/M phase, reduced cells in S phase, inhibited cell invasion and migration, decreased expressions of Ki67, Caspase-1, Gasdermin D, IL-1β and IL-18, and MMP-9 (all P<0.05). NLRP3 was the direct target of miR-223-3p. Moreover, compared with the miR-223-3p mimic group, the miR-223-3p mimic+oe-NLRP3 group showed increased expressions of NLRP3, Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9, promoted proliferation, invasion and migration, and increased cells in S phase (all P<0.05). The animal test revealed that compared with the mimic-NC+ oe- NC group, miR-223-3p mimic+ oe-NC group showed reduced tumor volume and decreased Ki67 expression (both P<0.05); while compared with miR-223-3p mimic+ oe-NC group, miR-223-3p mimic+ oe-NLRP3 group had increased tumor volume and increased Ki67 expression (both P<0.05). It was concluded that overexpression of miR-223-3p can effectively inhibit the expression of NLRP3 and cell pyroptosis in MDS.
2021-04-16 | p53 activation during ribosome biogenesis regulates normal erythroid differentiation.
The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis showed that ribosome biogenesis is abruptly interrupted by the decline in ribosomal DNA transcription and the collapse of ribosomal protein neosynthesis. Its premature arrest by the RNA Pol I inhibitor CX-5461 targeted the proliferation of immature erythroblasts. p53 was activated spontaneously or in response to CX-5461, concomitant to ribosome biogenesis arrest, and drove a transcriptional program in which genes involved in cell cycle-arrested, negative regulation of apoptosis, and DNA damage response were upregulated. RNA Pol I transcriptional stress resulted in nucleolar disruption and activation of the ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation is crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold downregulation of ribosome biogenesis could be prematurely reached and, together with pathological p53 activation, prevents a normal expansion of erythroid progenitors.
2016-09-13 | miR-378 inhibits cell growth and enhances apoptosis in human myelodysplastic syndromes
miR-378 has been proven to inhibit cell growth, migration and invasion in different types of cancers. In this study, we found that miR-378 was commonly downregulated in the bone marrow cells obtained from myelodysplastic syndrome (MDS) patients. We further investigated the role of miR-378 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the leukemic phase during the progression of MDS to AML (MDS/AML). Results indicated that overexpression of miR-378 in SKM-1 cells interfered with proliferation via inducing apoptosis and G0/G1-phase cell cycle arrest, and suppressive effect of miR-378 on MDS/AML cells may be mediated partly through Bcl-w and CDC40. Moreover, apoptosis induced by miR-378 correlated with increased expression of Bax and activation of caspase-3, -8 and -9. Taken together, our data support a critical role for miR-378 in the pathogenesis of MDS and provide a novel therapeutic target in this complex disease.
2016-08-30 | Identification of microRNA-regulated pathways using an integration of microRNA-mRNA microarray and bioinformatics analysis in CD34+ cells of myelodysplastic syndromes
Abstract The effect of microRNA (miRNA) and targeted mRNA on signal transduction is not fully understood in myelodysplastic syndromes (MDS). Here, we tried to identify the miRNAs-regulated pathways through a combination of miRNA and mRNA microarray in CD34+ cells from MDS patients. We identified 34 differentially expressed miRNAs and 1783 mRNAs in MDS. 25 dysregulated miRNAs and 394 targeted mRNAs were screened by a combination of Pearson’s correlation analysis and software prediction. Pathway analysis showed that several pathways such as Notch, PI3K/Akt might be regulated by those miRNA-mRNAs pairs. Through a combination of Pathway and miRNA-Gene or GO-Network analysis, miRNAs-regulated pathways, such as miR-195-5p/DLL1/Notch signaling pathway, were identified. Further qRT-PCR showed that miR-195-5p was up-regulated while DLL1 was down-regulated in patients with low-grade MDS compared with normal controls. Luciferase assay showed that DLL1 was a direct target of miR-195-5p. Overexpression of miR-195-5p led to increased cell apoptosis and reduced cell growth through inhibition of Notch signaling pathway. In conclusion, alteration expression of miRNAs and targeted mRNAs might have an important impact on cancer-related cellular pathways in MDS. Inhibition of Notch signaling pathway by miR-195-5p-DLL1 axis contributes to the excess apoptosis in low-grade MDS.
2015-11-11 | A ceRNA approach may unveil unexpected contributors to deletion syndromes, the model of 5q- syndrome
In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes. As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before. The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.
other
2026-09-20 | Lung-Predominant Hyperinflammatory Syndrome in Therapy-Related Myelodysplastic Syndrome Responsive to Interleukin-1 Blockade
Background/Objectives: In myelodysplastic neoplasms, autoinflammatory syndromes result from dysregulated innate immunity and cause severe, organ-dominant inflammation. Interleukin-1 signaling through the NLRP3 inflammasome is implicated in the pathogenesis of myelodysplastic disease and related inflammatory complications, especially in the context of RAS-pathway activation. Reports describing therapy-related myelodysplastic syndrome with pulmonary autoinflammatory syndromes are rare, and the efficacy of interleukin-1 blockade in this setting has not been previously documented. Results: A man in his 60s with therapy-related myelodysplastic syndrome (del 5q) following rectal chemoradiation developed a recurrent, lung-predominant autoinflammatory syndrome refractory to corticosteroids and Janus kinase inhibition. Next-generation sequencing identified gain-of-function mutations in NRAS, PTPN11, SF3B1, and ASXL1. On two separate occasions, anakinra produced rapid clinical improvement with normalization of inflammatory biomarkers and radiographic resolution; on both occasions, discontinuation of anakinra led to prompt relapse within days, with ferritin rising to above 5500 ng/mL and C-reactive protein exceeding 300 mg/L. Conclusions: This case demonstrates that interleukin-1-mediated inflammation can drive pulmonary complications in therapy-related myelodysplastic syndrome. Targeted cytokine blockade with anakinra produced reproducible and measurable clinical improvement when conventional therapies were insufficient. The recurrence of symptoms following anakinra withdrawal, and rapid improvement upon re-administration, underscores the functional link between interleukin-1-driven inflammation and clinical outcomes. The RAS/MAPK mutational context and the observed on–off response to anakinra further support an interleukin-1-driven mechanism that merits further investigation.
2025-11-23 | Monolobated megakaryocytes and ring sideroblasts: A morphological prelude to multihit TP53 and complex karyotype
A 76-year-old male with a history of localised pelvic radiotherapy for prostate cancer 6 years earlier presented with fatigue and severe pancytopenia (haemoglobin 80g/L, normocytic; platelets 50 × 109/L; leucocytes 1.5 × 109/L; neutrophils 0.3 × 109/L; no peripheral blasts). Bone marrow aspiration was hypercellular for age with erythroid hyperplasia and striking trilineage dysplasia. Erythroid precursors displayed nuclear irregularities, megaloblastoid changes and multinuclearity. Numerous small, monolobated megakaryocytes were present. Myeloblasts accounted for 4% of nucleated cells (left image, May–Grünwald stain, 100× lens objective). Iron staining revealed 43% ring sideroblasts (right image, Perls' staining, 100× lens objective). Cytogenetic analysis revealed a complex karyotype in which del(5q) and del(17p) were present across all metaphases: 47,XY,del(5)(q15q33),del(17)(p11.2),-18,-20,+21,+22,+mar[20]. Targeted next-generation sequencing (NGS) identified a likely pathogenic TP53 mutation (c.711G>A, p.Met237Ile) with a variant allele frequency (VAF) of 43%, in the absence of other myeloid-associated mutations, including SF3B1 and other spliceosome genes. According to recent classifications, the final diagnosis was myelodysplastic syndrome (MDS) with biallelic TP53 inactivation (WHO 2022)1/MDS with mutated TP53 (ICC 2022),2 corresponding to very high-risk disease by Molecular International Prognostic Scoring System (IPSS-M). Given the patient's prior exposure to pelvic radiotherapy for prostate cancer, the possibility of a post-cytotoxic therapy MDS (WHO 2022) or an MDS with the therapy-related qualifier (ICC 2022) cannot be excluded. This case underscores the value of integrated diagnostics. Initial morphology—monolobated megakaryocytes and ring sideroblasts—raised the possibility of MDS-del(5q) or MDS-SF3B1, but marked erythroid dysplasia and hyperplasia, atypical for isolated del(5q), indicated more aggressive biology. The detection of a complex karyotype and biallelic TP53 alterations ultimately reclassified this case. While del(5q) occurs in 10%–20% of MDS, only ~5% fit strict criteria for MDS with low blasts and isolated del(5q).1-3 Most are excluded due to excess blasts or additional cytogenetic changes, requiring reclassification. TP53 mutations occur in ~18% of del(5q) MDS, yet only biallelic alterations (4%–6%) associate with genomic instability, lenalidomide resistance and poor prognosis.4, 5 In such cases, TP53 status overrides other features in guiding disease behaviour and therapy. This case illustrates that, although cytomorphology offers useful clues, reliance solely on del(5q)-like features or ring sideroblasts risks misclassification, underscoring the importance of an integrated diagnostic approach. No funding was received for this research. The patient provided written informed consent prior to participation.
2025-07-09 | Characteristics of bone marrow cell dysplasia and its effectiveness in diagnosing myelodysplastic syndrome
Aim: The aim is to identify the distinctive morphological abnormalities in bone marrow cells and evaluate their accuracy and usefulness in diagnosing myelodysplastic syndrome. Materials and methods: This retrospective study analyzed 50 patients with dysplasia. Out of these, 20 patients were diagnosed with Myelodysplastic Syndromes (MDS) and 30 with non-clonal anemia. The MDS group had a median age of 42, while the non-clonal anemia group had a median age of 44, with no significant age difference (P > 0.05). MDS subtypes included MDS-SLD, MDS-MLD, MDS-RS, MDS-EB, MDS with isolated del(5q), and MDS-U. Data analysis was done using SSPS software. Results: The study included 50 participants, with 20 diagnosed with myelodysplastic syndromes (MDS) and 30 with non-clonal anemia. The groups were comparable in age and gender distribution, showing no significant differences. Among the MDS patients, the most common subtype was MDS with excess blasts (MDS-EB), followed by MDS with ring sideroblasts (MDS-RS), multi-lineage dysplasia (MDS-MLD), and single lineage dysplasia (MDS-SLD), with fewer cases of isolated del(5q) and unclassifiable MDS. Cytogenetic abnormalities were observed in 9 MDS cases, with trisomy 8 being the most frequent, followed by del(5q), −Y, and del(20q), indicating the cytogenetic diversity in MDS. In contrast, the non-clonal anemia group showed a varied distribution of subtypes, including immune thrombocytopenia (ITP), megaloblastic anemia, iron deficiency anemia, hemolytic anemia, and anemia of chronic disease. Significantly higher rates of dysplastic features—dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis—were found in the MDS group compared to the non-clonal anemia group (P< 0.05), underlining their diagnostic relevance in distinguishing MDS. Conclusion: This study demonstrates that the presence of significant dysplastic features and specific cytogenetic abnormalities plays a crucial role in distinguishing myelodysplastic syndromes (MDS) from non-clonal anemia, supporting the importance of comprehensive bone marrow evaluation in the diagnostic process.
2024-10-02 | Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa
Background Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. Methods By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55–95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1–54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4–156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Results Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS− patients achieved TI. Among 39 SF3B1 -positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. Conclusion We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.
2023-11-27 | ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression
Abstract A20‐binding inhibitor of NF‐κB activation (ABIN1) is a polyubiquitin‐binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin‐binding site ( Abin1 Q478H/Q478H ) is generated. These mice develop MDS‐like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1 Q478H/Q478H mice. Although Abin1 Q478H/Q478H cells are sensitive to RIPK1 kinase–RIPK3–MLKL‐dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase‐dead mutation. This indicates that the necroptosis‐independent function of RIPK3 is critical for anemia development in Abin1 Q478H/Q478H mice. Notably, Abin1 Q478H/Q478H mice exhibit higher levels of type I interferon (IFN‐I) expression in bone marrow cells compared towild‐type mice. Consistently, blocking type I IFN signaling through the co‐deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1 Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.
cell therapies
2024-04-17 | Co-occurrence of High-Risk Myelodysplastic Syndrome With a Complex Karyotype/TP53 Mutation and IgG Lambda Monoclonal Gammopathy of Undetermined Significance
Myelodysplastic syndrome (MDS) represents a group of hematologic disorders marked by abnormal cellular development in the bone marrow, while monoclonal gammopathy of undetermined significance (MGUS) involves abnormal plasma cells without symptomatic manifestations. This paper presents a compelling case of a 74-year-old Hispanic female diagnosed with a rare combination of high-risk MDS characterized by a complex karyotype and TP53 mutation, alongside IgG lambda MGUS. The patient's clinical presentation included a spectrum of symptoms such as body aches, rash, fever, dyspnea, and bloody watery diarrhea. Initial diagnostic evaluations yielded no significant findings, but subsequent investigations revealed abnormalities in both bone marrow and peripheral blood, indicative of coexisting MDS and MGUS. Chromosomal analysis further confirmed the presence of a complex karyotype with multiple aberrations, notably including 5q deletion. This case underscores the rarity of simultaneous high-risk MDS and MGUS, particularly with the additional complexity of a TP53 mutation and complex karyotype. It underscores the imperative for continued research efforts to elucidate the underlying mechanisms and optimal management strategies for such intricate cases. Moreover, it highlights the therapeutic challenges posed by concurrent MDS and plasma cell disorders, advocating for more aggressive interventions such as stem cell transplantation as potential avenues for improved patient outcomes.
2024-03-21 | Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.
Abstract A remarkably high rate of post‐transplant relapse in patients with TP53‐mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT ( N = 38) versus non‐HSCT ( N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non‐HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion ( p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non‐HSCT) had multi‐hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non‐HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow‐up was 15.1 months for HSCT and 5.7 months for non‐HSCT. Median disease‐free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non‐HSCT cohorts, respectively. Non‐relapse mortality at 12 months was 22% versus 44% for HSCT versus non‐HSCT. In the HSCT cohort, the rate of grade II–IV acute and chronic graft‐versus‐host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non‐HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53‐mutated MDS/AML remain an area of unmet clinical need.
2018-03-01 | Allogeneic Stem Cell Transplantation for Myelodysplastic Syndrome Patients with a 5q Deletion
Abstract
The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P < .001), whereas female recipient sex resulted in improved survival (hazard ratio, .61; 95% CI, .41 to .90; P = .01). We conclude that allogeneic HCT can cure a subset of patients with MDS and a del (5q) abnormality.
2014-02-10 | Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.
2009-02-24 | Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). However, the morbidity and mortality associated with conventional HSCT have traditionally prevented many patients from undergoing such treatment. Recent advances, including better prognostic algorithms, the introduction of reduced intensity conditioning regimens, and experience with alternative donors, have made HSCT a realistic option for an increasing number of patients with MDS.
proteins
2024-03-30 | Luspatercept in low-risk myelodysplastic syndromes: a paradigm shift in treatment strategies
In patients with myelodysplastic syndromes (MDS), anemia is prevalent affecting 80%-85% of low-risk (LR-MDS) patients, with 40% eventually requiring red blood cell (RBC) transfusions. Except forlenalidomide, exclusively approved for those with deletion of chromosome 5q,erythropoiesis-stimulating agents (ESAs) are the primary treatment choice for low-risk patients. Those unresponsive to ESAs face limited alternatives, eventually necessitating long-term RBC transfusions, leading to secondary iron overload and adversely affecting quality of life (QoL). Luspatercept is a pioneering erythroid maturation agent. It received approval by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for treating adults experiencing transfusion-dependent anemia associated with LR-MDS or β-thalassemia. Recently, the FDA approved luspatercept as first- line therapy in patients with very low- to intermediate-risk MDS who require RBC transfusions and have not previously received ESAs. This review summarizes the historical impact of luspatercept intreating LR-MDS unresponsive to ESAs and illustrates its potential benefit asfrontline therapy in MDS and its employment in patients with myelofibrosis-induced anemia. Luspatercept has revolutionized the therapeutic paradigm of LR-MDS, for which there was a limited therapeutic arsenal, especially in the setting of patients who did not respond or fail after ESA treatment.
2023-11-01 | [Recent findings in myelodysplastic syndrome].
Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myeloid leukemia (AML).Recent developments include the classification and the estimation of prognosis. In 2022 the former 2016 WHO classification was replaced by the ICC and WHO 2022 classification. Both classifications have included precursor lesions (CHIP and ICUS), both distinguish between three molecularly cytogenetically defined subgroups - del(5q), TP53, SF3B1 - and morphologically defined subgroups with differences in blast threshold (WHO: 20%; ICC: 10%) for the differentiation from AML. However, although prognostic factors influenced the classification-subgroups, it is important to distinguish the prognosis, which is crucial for optimal therapeutic decision making. Since 2022, the IPSS-M has been available for this purpose, which represents an expansion of the well-established IPSS-R. It could improve prognosis estimation by adding molecular data, recently this could have been confirmed in real world cohorts. The IPSS-M also represents an important extension with regard to prognosis estimation for patients with therapy-related MDS.In 2020 Luspatercept has been approved for transfusion-dependent lower risk MDS patients harboring ring sideroblasts ± an SF3B1 mutation after failure of an erythropoiesis stimulating agent. The COMMANDS trial has just reported an interim analysis, where the superiority of luspatercept in the 1st line compared to erythropoietin could be demonstrated. In addition, data from the phase III trial with Imeltelstat give reason to hope that we will be able to offer a new second-line therapy to LR-MDS patients. For higher risk MDS patients azacitidine therapy remains the standard of care, results of phase III trials of combination therapies must be awaited.NEUERUNGEN – KLASSIFIKATION UND PROGNOSE: Die WHO-2016-Klassifikation wurde durch die ICC und die Klassifikation der WHO 2022 abgelöst. Die beiden Klassifikationen weisen viele Ähnlichkeiten auf; den größten Unterschied stellt der Blastengrenzwert dar. Seit 2022 steht der IPSS-M, der molekulare Aberrationen berücksichtigt, zur Verfügung und verbessert im Vergleich zum IPSS-R die Prognosegenauigkeit für das progressionsfreie Überleben und das Gesamtüberleben. Somit soll eine optimierte therapeutische Entscheidungsfindung ermöglicht werden. NEUERUNGEN – THERAPIE: 2020 wurde Luspatercept für transfusionsabhängige Patient*innen mit Ringsideroblasten ± einer SF3B1-Mutation zugelassen. Rezent konnte die Überlegenheit von Luspatercept in der ersten Linie gegenüber EPO gezeigt werden. Mit Imetelstat können wir in Zukunft ggf. eine neue Zweitlinientherapie für LR-MDS-Patient*innen nach Versagen von EPO anbieten. Für High-Risk-Patient*innen ist die Therapie mit Azacitidin weiterhin der Therapiestandard – die Ergebnisse der Phase-III-Studien der Kombinationstherapien müssen abgewartet werden.
2023-07-03 | Why do we not have more drugs approved for MDS? A critical viewpoint on novel drug development in MDS.
Approval of new agents to treat higher risk (HR) myelodysplastic syndrome (MDS) has stalled since the approval of DNA methyltransferase inhibitors (DNMTi). In addition, the options for patients with lower risk (LR) MDS who have high transfusion needs and do not harbor ring sideroblasts or 5q- syndrome are limited. Here, we review the current treatment landscape in MDS and identify areas of unmet need, such as treatment after failure of erythropoiesis-stimulating agents or DNMTis, TP53-mutated disease, and MDS with potentially targetable mutations. We discuss how our understanding of MDS pathogenesis can inform therapy development, including treating HR-MDS similarly to AML and pursuing therapies to address splicing factor mutations and dysregulated inflammation. We then bring a critical lens to current methodology of MDS studies and propose solutions to improve the efficiency and yield of these clinical trials, including using the most meaningful response metrics and expanding enrollment.
2019-07-05 | [Treatment for low-risk myelodysplastic syndromes].
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenia and leukemic transformation. Allogeneic hematopoietic stem cell transplantation is the only potential curative therapy for MDS; however, the first treatment option for transfusion-independent patients with low-risk MDS remains limited. Recently, lenalidomide has become available for patients with low-risk MDS and symptomatic anemia with del (5q) (5q-syndrome), darbepoetin (DA) for those with anemia without del (5q), and azacitidine for those with DA-resistant anemia or anemia with thrombocytopenia. DA may be the first treatment option for anemic patients with low-risk MDS because the incidence of 5q-syndrome is rare in Japan in contrast to western countries. It has been reported that primary or secondary failure of Erythropoiesis-stimulating agents (ESA) correlated with a higher risk of acute myeloid leukemia, and none of the leading second-line treatments significantly improved survival. In this review, I have described the treatment strategies in using such drugs and future perspectives for low-risk MDS.
2016-12-07 | Erythropoiesis‐stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower‐risk myelodysplastic syndrome
Abstract Background The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower‐risk myelodysplastic syndrome ( MDS ) from 17 European countries from both university hospitals and smaller regional hospitals. Objective The aim of this study was to describe the usage and clinical impact of erythropoiesis‐stimulating agents ( ESA s) in 1696 patients enrolled between 2008 and 2014. Methods The effects of ESA s on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. Results ESA treatment (median duration of 27.5 months, range 0–77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit ( HR 0.82, 95% CI: 0.65–1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions ( P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post‐ ESA treatment transfusion was 6.1 months (IQR: 4.3–15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0–47.8 months) in patients without prior transfusions ( HR 2.4, 95% CI: 1.7–3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death ( HR 0.65, 95% CI: 0.45–0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia ( HR 0.71, 95% CI: 0.39–1.29, P = 0.27). Conclusion Appropriate use of ESA s can significantly delay the onset of a regular transfusion need in patients with lower‐risk MDS .
small molecules
2026-08-20 | Isolated del(5q) with myeloproliferative driver mutations: A systematic review of published cases and clinical implications.
Myeloid neoplasms harboring both an isolated deletion of chromosome 5q (del(5q)) and myeloproliferative neoplasm (MPN) driver mutations (JAK2, CALR, MPL) constitute a rare and diagnostically challenging subset, often described with features overlapping those of myelodysplastic syndromes (MDS) and MPN. We systematically reviewed published case reports and case series of adult patients with myeloid neoplasms and concomitant isolated del(5q) and MPN driver mutations. A comprehensive search of PubMed and Google Scholar from inception through 31 December 2024 was performed using terms related to "del(5q)", "JAK2", "CALR", "MPL", and "myeloid neoplasm". Eligible reports required documentation of isolated del(5q) and at least one MPN driver mutation with extractable clinical, cytogenetic, and/or molecular data. Data were synthesised descriptively; no quantitative meta-analysis was feasible. The review followed PRISMA 2020 guidelines and was registered post-study at INPLASY2025120046. Twenty publications reporting 24 patients (diagnosed between 2006 and 2021) met the inclusion criteria. The median age was 70.5 years with a female predominance. Most patients presented with macrocytic anemia, thrombocytosis, and megakaryocytic dysplasia, frequently accompanied by marrow fibrosis. JAK2 V617F was the predominant mutation, whereas CALR and MPL were rarely described. Lenalidomide achieved hematologic responses in 14 of 17 evaluable patients and cytogenetic responses in 8 of 16; JAK2 V617F clearance occurred in 4 of 13. During a median follow-up of approximately two years, 5 of 24 patients progressed to acute myeloid leukemia. Reported cases with isolated del(5q) and an MPN driver mutation suggest a rare overlap presentation with mixed dysplastic and proliferative features. Lenalidomide appears to provide hematologic and cytogenetic benefit in some patients, although molecular persistence and progression to AML have been observed. Given the limited number and heterogeneity of published cases, these observations should be interpreted with caution. Larger, systematically collected datasets are needed to better understand the clinical significance and optimal management of this combination.
2026-08-19 | ALK-fusion-positive non-small cell lung cancer concomitant with 5q deletion myelodysplastic syndrome: a case report
Multiple primary malignant neoplasms (MPMNs) refers to the concurrent or sequential development of at least two distinct primary malignant tumors within the body, arising from the same organ or different organs. The current manuscript discusses the unique clinical case of a female patient diagnosed with concomitant metastatic ALK-positive NSCLC and del 5q-MDS and was treated for both entities with oral systemic treatments only with a remarkable response for both diseases.
2026-06-17 | The role of adding a hormonal component to the pathogenetic therapy of myelodysplastic syndrome
Background. In myelodysplastic syndrome (MDS), an imbalance of interleukins causes increased apoptosis of hematopoietic stem cells, i.e. cytopenia. Activation of inflammasomes due to specific mutations, for example, SF3B1 or del(5q), is associated with different cytokine profiles and inflammatory phenotypes. Objective: to study the levels of pro-inflammatory and anti-inflammatory interleukins against the background of adjuvant hormonal therapy in patients with MDS. Materials and methods. Three clinical observation groups were formed, in which patients were assigned the appropriate treatment: lenalidomide according to the monotherapy regimen (L group), lenalidomide and dexamethasone p/o tablet 3 mg per day in the first month and 1 mg in the next 2 months (LD group), as well as lenalidomide and prednisolone p/o tablet 15 mg per day in the first month and 10 mg in the next 2 months (LP group). Before and after treatment (in 3 months), the levels of pro-inflammatory and anti-inflammatory cytokines were assessed. Results. The effectiveness of adjuvant hormonal anti-inflammatory therapy in patients with MDS receiving treatment with lenalidomide was established. A decrease in proinflammatory IL-6 levels from 9.2 ± 1.1 to 6.7 ± 0.8 pg/ml in participants receiving dexamethasone, and from 8.8 ± 1.3 to 4.9 ± 1.8 pg/ml in those receiving prednisone indicates the benefit of using hormonal drugs to reduce systemic inflammation in MDS. No less significant for clinical practice was a decrease demonstrated by IL-1β in the group receiving prednisone together with lenalidomide: from 12.8 ± 2.0 to 5.8 ± 1.3 pg/ml, the result is significant compared to the indicators before treatment, as well as to the L group, p < 0.05. At the same time, an important result was an increase in the level of anti-inflammatory interleukins: IL-4 against the background of taking prednisolone and IL-10 in the group of patients who were prescribed dexamethasone. Conclusions. The prescription of hormonal adjuvant therapy led to a decrease in the levels of pro-inflammatory interleukins and an increase in anti-inflammatory ones. At the same time, in the group of patients who took only lenalidomide without hormones, the concentration of TNF-α in serum increased from 8.4 ± 2.0 to 12.2 ± 2.2 pg/ml. Research on the effectiveness of adjuvant protocols in the comprehensive treatment of MDS must be continued, because any therapeutic intervention that reduces the intensity of systemic inflammation and can potentially improve the quality of life of patients and the prognosis of the disease justifiably deserves the attention of scientists and clinicians
2026-06-01 | Mutational dynamics in patients with del(5q) MDS treated with lenalidomide prior to transfusion dependency—Molecular results from the Sintrarev clinical trial
Abstract Lenalidomide (Len) is the standard of care for red blood cell transfusion‐dependent (TD) patients with myelodysplastic syndromes (MDS) and del(5q). A Phase III clinical trial (SintraRev) demonstrated better efficacy of early treatment with Len in anemic del(5q) MDS patients prior to TD, but clonal evolution with this approach remained unexplored. We evaluated changes in mutational profiles of non‐TD del(5q) MDS patients treated with Len to assess whether early administration of Len could reduce or worsen the mutational burden in those patients. The molecular profile of patients included in the SintraRev trial was analyzed by targeted sequencing. Median follow up of patients was 60.6 months (interquartile range [IQR] 32.3–73.9). Next‐generation sequencing (NGS) was available in a total of 51 patients. SF3B1 (25.5%) and TP53 (21.3%) were the most frequently mutated genes. Clonal evolution during treatment among patients receiving Len or placebo (Pcb) was markedly different, with a 41.2% reduction in predominating clones in the Len arm, while remaining stable/increase in 100% of Pcb patients after 2 years. Mutations in SF3B1 and TP53 decreased/remained stable in the Len cohort, while only DNMT3A mutations increased under cytogenetic response. Regarding disease progression, only 20% of Len patients carrying TP53 mutations developed acute myeloid leukemia (AML), similar to the Pcb group (20%). Treatment with low‐dose Len in transfusion‐independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53 ‐mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.
2026-04-07 | Association between treatment-emergent cytopenias and clinical responses to imetelstat in lower-risk myelodysplastic syndromes
Myelodysplastic syndromes/neoplasms (MDS) are myeloid malignancies with ineffective hematopoiesis, resulting in variable cytopenias and increased risk of progression to acute myeloid leukemia (AML) [ 1 , 2 ]. Imetelstat, a first-in-class competitive telomerase inhibitor, is an approved therapy in the US and Europe for adults with lower-risk MDS (LR-MDS) with red blood cell (RBC) transfusion-dependent (TD) anemia who are relapsed or refractory to, or ineligible for, erythropoiesis-stimulating agents (ESAs) [ 3 , 4 ]. In the Phase III IMerge trial (NCT02598661), a significantly higher proportion of patients on imetelstat achieved RBC transfusion independence (TI) than placebo [ 5 ]. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (68%) and thrombocytopenia (62%), mostly occurring within the first 3 cycles of imetelstat [ 5 ]. These events were generally transient and associated with similarly low rates of grade 3/4 clinical consequences (bleeding, infection, and febrile neutropenia) as placebo [ 5 ]. As neutropenia and thrombocytopenia occurring early with lenalidomide treatment have been correlated with clinical response in patients with del(5q) LR-MDS, suggesting an on-target, disease-modifying effect on the del(5q) clone [ 6 ], we conducted a post hoc analysis to evaluate the association between early treatment-emergent cytopenias with imetelstat and clinical responses.
oligonucleotides
2022-02-28 | Effect of miR-223-3p on cell pyroptosis in myelodysplastic syndrome and its mechanism via regulating the expression of NLRP3
This study aimed to investigate the regulatory mechanism of the miR-223-3p/NLRP3 signaling axis in the progression of myelodysplastic syndrome (MDS). For this purpose, SKM-1 cells were transfected and three groups were set up according to different transfection protocols: si-NC group (NLRP3 silencing negative control plasmid), si-NLRP3 group (NLRP3 silencing plasmid), miR-223-3p mimic- NC group (miR-223-3p overexpressing negative control plasmid), miR-223-3p mimic group (miR-223- 3p overexpressing plasmid), miR-223-3p mimic+oe-NLRP3 group and miR-223-3p mimic+oe-NLRP3 group (NLRP3 silencing combined with miR-223-3p overexpressing plasmid). Normal bone marrow cells were used as the control. qRT-PCR was used to detect relative expressions of NLRP3 and miR- 223-3p; and Western blot to detect Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9 expressions. Cell proliferation detection used CCK-8 assay, cell cycle distribution detection adopted flow cytometry, and cell migration and invasion analyses relied on Transwell assay. Dual-luciferase reporter assay verified the relationship between NLRP3 and miR-223-3p. An animal experiment was finally conducted to confirm the results obtained in cells. Results showed that compared with normal bone marrow cells and K562 cells, there were significantly upregulated NLRP3 expression and upregulated expression of miR-223-3p in SKM-1 cells (all P<0.05). Compared with the si-NC group and mimic-NC group respectively, the si-NLRP3 group and miR-223-3p mimic group showed inhibited proliferation, blocked cells in the G0/M phase, reduced cells in S phase, inhibited cell invasion and migration, decreased expressions of Ki67, Caspase-1, Gasdermin D, IL-1β and IL-18, and MMP-9 (all P<0.05). NLRP3 was the direct target of miR-223-3p. Moreover, compared with the miR-223-3p mimic group, the miR-223-3p mimic+oe-NLRP3 group showed increased expressions of NLRP3, Ki67, Caspase-1, Gasdermin D, IL-1β, IL-18 and MMP-9, promoted proliferation, invasion and migration, and increased cells in S phase (all P<0.05). The animal test revealed that compared with the mimic-NC+ oe- NC group, miR-223-3p mimic+ oe-NC group showed reduced tumor volume and decreased Ki67 expression (both P<0.05); while compared with miR-223-3p mimic+ oe-NC group, miR-223-3p mimic+ oe-NLRP3 group had increased tumor volume and increased Ki67 expression (both P<0.05). It was concluded that overexpression of miR-223-3p can effectively inhibit the expression of NLRP3 and cell pyroptosis in MDS.
2021-04-16 | p53 activation during ribosome biogenesis regulates normal erythroid differentiation.
The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis showed that ribosome biogenesis is abruptly interrupted by the decline in ribosomal DNA transcription and the collapse of ribosomal protein neosynthesis. Its premature arrest by the RNA Pol I inhibitor CX-5461 targeted the proliferation of immature erythroblasts. p53 was activated spontaneously or in response to CX-5461, concomitant to ribosome biogenesis arrest, and drove a transcriptional program in which genes involved in cell cycle-arrested, negative regulation of apoptosis, and DNA damage response were upregulated. RNA Pol I transcriptional stress resulted in nucleolar disruption and activation of the ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation is crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold downregulation of ribosome biogenesis could be prematurely reached and, together with pathological p53 activation, prevents a normal expansion of erythroid progenitors.
2016-09-13 | miR-378 inhibits cell growth and enhances apoptosis in human myelodysplastic syndromes
miR-378 has been proven to inhibit cell growth, migration and invasion in different types of cancers. In this study, we found that miR-378 was commonly downregulated in the bone marrow cells obtained from myelodysplastic syndrome (MDS) patients. We further investigated the role of miR-378 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the leukemic phase during the progression of MDS to AML (MDS/AML). Results indicated that overexpression of miR-378 in SKM-1 cells interfered with proliferation via inducing apoptosis and G0/G1-phase cell cycle arrest, and suppressive effect of miR-378 on MDS/AML cells may be mediated partly through Bcl-w and CDC40. Moreover, apoptosis induced by miR-378 correlated with increased expression of Bax and activation of caspase-3, -8 and -9. Taken together, our data support a critical role for miR-378 in the pathogenesis of MDS and provide a novel therapeutic target in this complex disease.
2016-08-30 | Identification of microRNA-regulated pathways using an integration of microRNA-mRNA microarray and bioinformatics analysis in CD34+ cells of myelodysplastic syndromes
Abstract The effect of microRNA (miRNA) and targeted mRNA on signal transduction is not fully understood in myelodysplastic syndromes (MDS). Here, we tried to identify the miRNAs-regulated pathways through a combination of miRNA and mRNA microarray in CD34+ cells from MDS patients. We identified 34 differentially expressed miRNAs and 1783 mRNAs in MDS. 25 dysregulated miRNAs and 394 targeted mRNAs were screened by a combination of Pearson’s correlation analysis and software prediction. Pathway analysis showed that several pathways such as Notch, PI3K/Akt might be regulated by those miRNA-mRNAs pairs. Through a combination of Pathway and miRNA-Gene or GO-Network analysis, miRNAs-regulated pathways, such as miR-195-5p/DLL1/Notch signaling pathway, were identified. Further qRT-PCR showed that miR-195-5p was up-regulated while DLL1 was down-regulated in patients with low-grade MDS compared with normal controls. Luciferase assay showed that DLL1 was a direct target of miR-195-5p. Overexpression of miR-195-5p led to increased cell apoptosis and reduced cell growth through inhibition of Notch signaling pathway. In conclusion, alteration expression of miRNAs and targeted mRNAs might have an important impact on cancer-related cellular pathways in MDS. Inhibition of Notch signaling pathway by miR-195-5p-DLL1 axis contributes to the excess apoptosis in low-grade MDS.
2015-11-11 | A ceRNA approach may unveil unexpected contributors to deletion syndromes, the model of 5q- syndrome
In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes. As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before. The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.
other
2026-09-20 | Lung-Predominant Hyperinflammatory Syndrome in Therapy-Related Myelodysplastic Syndrome Responsive to Interleukin-1 Blockade
Background/Objectives: In myelodysplastic neoplasms, autoinflammatory syndromes result from dysregulated innate immunity and cause severe, organ-dominant inflammation. Interleukin-1 signaling through the NLRP3 inflammasome is implicated in the pathogenesis of myelodysplastic disease and related inflammatory complications, especially in the context of RAS-pathway activation. Reports describing therapy-related myelodysplastic syndrome with pulmonary autoinflammatory syndromes are rare, and the efficacy of interleukin-1 blockade in this setting has not been previously documented. Results: A man in his 60s with therapy-related myelodysplastic syndrome (del 5q) following rectal chemoradiation developed a recurrent, lung-predominant autoinflammatory syndrome refractory to corticosteroids and Janus kinase inhibition. Next-generation sequencing identified gain-of-function mutations in NRAS, PTPN11, SF3B1, and ASXL1. On two separate occasions, anakinra produced rapid clinical improvement with normalization of inflammatory biomarkers and radiographic resolution; on both occasions, discontinuation of anakinra led to prompt relapse within days, with ferritin rising to above 5500 ng/mL and C-reactive protein exceeding 300 mg/L. Conclusions: This case demonstrates that interleukin-1-mediated inflammation can drive pulmonary complications in therapy-related myelodysplastic syndrome. Targeted cytokine blockade with anakinra produced reproducible and measurable clinical improvement when conventional therapies were insufficient. The recurrence of symptoms following anakinra withdrawal, and rapid improvement upon re-administration, underscores the functional link between interleukin-1-driven inflammation and clinical outcomes. The RAS/MAPK mutational context and the observed on–off response to anakinra further support an interleukin-1-driven mechanism that merits further investigation.
2025-11-23 | Monolobated megakaryocytes and ring sideroblasts: A morphological prelude to multihit TP53 and complex karyotype
A 76-year-old male with a history of localised pelvic radiotherapy for prostate cancer 6 years earlier presented with fatigue and severe pancytopenia (haemoglobin 80g/L, normocytic; platelets 50 × 109/L; leucocytes 1.5 × 109/L; neutrophils 0.3 × 109/L; no peripheral blasts). Bone marrow aspiration was hypercellular for age with erythroid hyperplasia and striking trilineage dysplasia. Erythroid precursors displayed nuclear irregularities, megaloblastoid changes and multinuclearity. Numerous small, monolobated megakaryocytes were present. Myeloblasts accounted for 4% of nucleated cells (left image, May–Grünwald stain, 100× lens objective). Iron staining revealed 43% ring sideroblasts (right image, Perls' staining, 100× lens objective). Cytogenetic analysis revealed a complex karyotype in which del(5q) and del(17p) were present across all metaphases: 47,XY,del(5)(q15q33),del(17)(p11.2),-18,-20,+21,+22,+mar[20]. Targeted next-generation sequencing (NGS) identified a likely pathogenic TP53 mutation (c.711G>A, p.Met237Ile) with a variant allele frequency (VAF) of 43%, in the absence of other myeloid-associated mutations, including SF3B1 and other spliceosome genes. According to recent classifications, the final diagnosis was myelodysplastic syndrome (MDS) with biallelic TP53 inactivation (WHO 2022)1/MDS with mutated TP53 (ICC 2022),2 corresponding to very high-risk disease by Molecular International Prognostic Scoring System (IPSS-M). Given the patient's prior exposure to pelvic radiotherapy for prostate cancer, the possibility of a post-cytotoxic therapy MDS (WHO 2022) or an MDS with the therapy-related qualifier (ICC 2022) cannot be excluded. This case underscores the value of integrated diagnostics. Initial morphology—monolobated megakaryocytes and ring sideroblasts—raised the possibility of MDS-del(5q) or MDS-SF3B1, but marked erythroid dysplasia and hyperplasia, atypical for isolated del(5q), indicated more aggressive biology. The detection of a complex karyotype and biallelic TP53 alterations ultimately reclassified this case. While del(5q) occurs in 10%–20% of MDS, only ~5% fit strict criteria for MDS with low blasts and isolated del(5q).1-3 Most are excluded due to excess blasts or additional cytogenetic changes, requiring reclassification. TP53 mutations occur in ~18% of del(5q) MDS, yet only biallelic alterations (4%–6%) associate with genomic instability, lenalidomide resistance and poor prognosis.4, 5 In such cases, TP53 status overrides other features in guiding disease behaviour and therapy. This case illustrates that, although cytomorphology offers useful clues, reliance solely on del(5q)-like features or ring sideroblasts risks misclassification, underscoring the importance of an integrated diagnostic approach. No funding was received for this research. The patient provided written informed consent prior to participation.
2025-07-09 | Characteristics of bone marrow cell dysplasia and its effectiveness in diagnosing myelodysplastic syndrome
Aim: The aim is to identify the distinctive morphological abnormalities in bone marrow cells and evaluate their accuracy and usefulness in diagnosing myelodysplastic syndrome. Materials and methods: This retrospective study analyzed 50 patients with dysplasia. Out of these, 20 patients were diagnosed with Myelodysplastic Syndromes (MDS) and 30 with non-clonal anemia. The MDS group had a median age of 42, while the non-clonal anemia group had a median age of 44, with no significant age difference (P > 0.05). MDS subtypes included MDS-SLD, MDS-MLD, MDS-RS, MDS-EB, MDS with isolated del(5q), and MDS-U. Data analysis was done using SSPS software. Results: The study included 50 participants, with 20 diagnosed with myelodysplastic syndromes (MDS) and 30 with non-clonal anemia. The groups were comparable in age and gender distribution, showing no significant differences. Among the MDS patients, the most common subtype was MDS with excess blasts (MDS-EB), followed by MDS with ring sideroblasts (MDS-RS), multi-lineage dysplasia (MDS-MLD), and single lineage dysplasia (MDS-SLD), with fewer cases of isolated del(5q) and unclassifiable MDS. Cytogenetic abnormalities were observed in 9 MDS cases, with trisomy 8 being the most frequent, followed by del(5q), −Y, and del(20q), indicating the cytogenetic diversity in MDS. In contrast, the non-clonal anemia group showed a varied distribution of subtypes, including immune thrombocytopenia (ITP), megaloblastic anemia, iron deficiency anemia, hemolytic anemia, and anemia of chronic disease. Significantly higher rates of dysplastic features—dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis—were found in the MDS group compared to the non-clonal anemia group (P< 0.05), underlining their diagnostic relevance in distinguishing MDS. Conclusion: This study demonstrates that the presence of significant dysplastic features and specific cytogenetic abnormalities plays a crucial role in distinguishing myelodysplastic syndromes (MDS) from non-clonal anemia, supporting the importance of comprehensive bone marrow evaluation in the diagnostic process.
2024-10-02 | Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa
Background Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. Methods By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55–95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1–54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4–156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Results Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS− patients achieved TI. Among 39 SF3B1 -positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. Conclusion We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.
2023-11-27 | ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression
Abstract A20‐binding inhibitor of NF‐κB activation (ABIN1) is a polyubiquitin‐binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin‐binding site ( Abin1 Q478H/Q478H ) is generated. These mice develop MDS‐like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1 Q478H/Q478H mice. Although Abin1 Q478H/Q478H cells are sensitive to RIPK1 kinase–RIPK3–MLKL‐dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase‐dead mutation. This indicates that the necroptosis‐independent function of RIPK3 is critical for anemia development in Abin1 Q478H/Q478H mice. Notably, Abin1 Q478H/Q478H mice exhibit higher levels of type I interferon (IFN‐I) expression in bone marrow cells compared towild‐type mice. Consistently, blocking type I IFN signaling through the co‐deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1 Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality.
5 orphan drug designations for Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ivosidenib | small molecules | EMA | Les Laboratoires Servier | |
Cedazuridine, Decitabine [Inaqovi] | small molecules | EMA | Otsuka Pharmaceutical Netherlands B.V. | |
Sabatolimab | antibodies | EMA | Novartis Europharm Limited | |
Azacitidine [Vidaza] | small molecules | EMA | Celgene Europe B.V. | |
Arsenic trioxide [Trisenox] | small molecules | EMA | [INACTIVE] Cephalon Europe |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.