RARE DISEASE
Acute myeloid leukemia with recurrent genetic anomaly
Acute myeloid leukemia with recurrent genetic anomaly
Acute myeloid leukemia with recurrent genetic anomaly
Synonyms: AML with recurrent genetic anomaly
Synonyms: AML with recurrent genetic anomaly
Synonyms: AML with recurrent genetic anomaly
Drug discovery
1
drug
With orphan designation
Overview
Acute myeloid leukemia (AML) with recurrent genetic abnormalities is a molecularly defined subtype characterized by specific chromosomal translocations (e.g., CBFB-MYH11, RUNX1-RUNX1T1) or mutations (e.g., NPM1, biallelic CEBPA) that drive leukemogenesis and inform prognosis. These genetic alterations guide risk stratification and therapeutic choices, with favorable-risk cases (e.g., core-binding factor AML) showing improved survival but relapsing in ~40% of cases [1][6][16]. FLT3 mutations, common in these subgroups, complicate prognosis and necessitate targeted approaches [1][8].
Therapies
Induction: Anthracycline/cytarabine (7+3 regimen) ± FLT3 inhibitors (midostaurin) for FLT3-mutant cases [5][8][13].
Consolidation: High-dose cytarabine or allogeneic stem cell transplantation for intermediate/adverse-risk cases [5][8].
Targeted therapies: Gemtuzumab ozogamicin (CD33) in core-binding factor AML and azacitidine maintenance post-remission [13][15].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
155 drug discovery papers about Acute myeloid leukemia with recurrent genetic anomaly, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
155 drug discovery papers about Acute myeloid leukemia with recurrent genetic anomaly, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.
Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.
2026-05-15 | TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition.
TP53-mutated acute myeloid leukemia (AML) represents a particularly aggressive and therapeutically refractory subtype of the disease. While recurrent chromosomal abnormalities such as -5/del(5q), -7/del(7q), and del(17p) are well studied in this context, additional co-occurring events remain less well defined. Using the multidimensional Leucegene dataset (~700 primary AML specimens), we identified and comprehensively characterized a distinct subset of TP53-altered AML marked by recurrent deletions on the short arm of chromosome 3 [del(3p), >20% TP53-mutated cases]. These deletions frequently co-occur with del(5q) and encompass several ribosomal protein genes (RPGs), leading to a global down-regulation of the ribosomal network and reduced protein synthesis. We show that this ribosomopathy-like phenotype is most pronounced in TP53-mutated cases with combined RPG deletions on chromosomes 3p and 5q, suggesting a cooperative oncogenic mechanism. Chemical screening identified HSP90 inhibition as a selective vulnerability in AML with low RPG expression. These findings highlight a previously unappreciated TP53-altered AML subset characterized by converging genomic and translational defects and suggest that ribosomal stress may serve as a therapeutic entry point for targeted intervention of this patient subgroup.
2026-03-30 | Aggressive extramedullary acute myeloid leukaemia masquerading as dental infection with rare t(10:11) translocation and subsequent relapse as leukaemia cutis.
Extramedullary leukaemia, also known as myeloid sarcoma, is a rare manifestation of acute myeloid leukaemia (AML) that typically occurs in conjunction with bone marrow involvement. It is characterized by infiltration of leukemic cells into extramedullary tissues, including the skin, soft tissues, and lymph nodes, where it may present as mass-like or nodular lesions. When associated with high-risk cytogenetic abnormalities, extramedullary disease may exhibit particularly aggressive behaviour and pose substantial diagnostic challenges, especially when it precedes or masks systemic manifestations of AML. A 36-year-old postpartum woman, 6 months following delivery, presented with a 3-month history of progressively enlarging nodules involving the left side of the face. These lesions were initially attributed to a dental infection following extraction of two teeth; however, they persisted and progressed despite appropriate dental treatment. In the weeks preceding this presentation, the patient had developed worsening fatigue, dyspnoea, jaundice, and easy bruising. On examination, there were several firms, non-tender nodules over the left cheek, prominent left cervical lymphadenopathy, scleral icterus, and diffuse ecchymoses. Laboratory results showed pancytopenia with severe anaemia, thrombocytopenia, and neutropenia, elevated liver enzymes suggestive of systemic involvement. The initial differential diagnosis included chronic infection, granulomatous disease, and hematologic malignancy. Following this, imaging showed multifocal facial soft-tissue masses and extensive cervical lymphadenopathy. Core biopsy of a cheek lesion showed diffuse infiltration by atypical myeloid cells consistent with extramedullary AML with monocytic differentiation, which was confirmed on bone marrow biopsy. Cytogenetic analysis revealed a t(10;11)(p13;q13.3), an additional der (20) t(1;20)(q21;q13.3), and a marker chromosome. Induction chemotherapy with cytarabine and idarubicin was initiated. Following consolidation therapy, the patient developed new cutaneous nodules and plaques several weeks later, and skin biopsy confirmed leukaemia cutis, indicating persistent extramedullary disease. This case illustrates a rare and aggressive presentation of extramedullary AML with monocytic differentiation and high-risk cytogenetics in a young postpartum patient, initially mimicking a localized odontogenic infection. The delayed diagnosis underscores the complexity of recognizing extramedullary leukaemia, particularly when early hematologic abnormalities are subtle or absent. The presence of a t(10;11) translocation and the subsequent development of leukaemia cutis following induction therapy highlight the aggressive biologic behaviour of this disease and reinforce the importance of heightened clinical suspicion, prompt tissue diagnosis, and vigilant surveillance for extramedullary relapse, which may require intensified therapeutic approaches.
2025-09-03 | Ruxolitinib and decitabine plus a busulfan-cyclophosphamide conditioning regimen for relapse prophylaxis in patients with high-risk acute myeloid leukemia or myelodysplastic syndromes.
Relapse remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome-IB (MDS-IB) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib has demonstrated antileukemic activity in vitro, and decitabine has been found to be tolerable when combined with modified busulfan-cyclophosphamide (mBu/Cy) conditioning regimen. Here, we investigated the efficacy of ruxolitinib and decitabine plus a mBu/Cy conditioning regimen (Rux-Dec-mBu/Cy) in reducing relapse in high-risk AML/MDS patients (ClinicalTrials.gov identifier: NCT04582604). This prospective investigational study enrolled 58 patients between May 2020 and July 2023. These patients had either a relapsed/refractory status, remission status with adverse genetic abnormalities or positive measurable residual disease (MRD+) prior to conditioning. Ruxolitinib (days -15 to -1) and decitabine (days -15 to -10) were administered, followed by mBu/Cy conditioning. The outcomes of a historical cohort of 58 patients (matched 1:1) who received mBu/Cy are described for reference. All 58 patients achieved engraftment. With a median follow-up of 967 (464-1597) days, the 2-year cumulative incidence of relapse was 19.0%. The probabilities of 2-year overall survival (OS), disease-free survival (DFS) and graft-versus-host disease-free, relapse-free survival (GRFS) were 70.3%, 70.6% and 65.2%, respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 44.1%. The most common grade ≥3 adverse event was oropharyngeal mucositis (8.6%, n=5). Within 6 months post-transplantation, the cumulative incidence of cytomegalovirus (CMV) reactivation was 34.5%, and that of Epstein-Barr virus (EBV) reactivation was 62.1%. This investigational study revealed that the Rux-Dec-mBu/Cy conditioning was tolerable and reduced relapse in high-risk AML/MDS patients.
2025-02-04 | Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.
cell therapies
2026-03-29 | The diagnostic potential of nanobodies in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a heterogeneous hematologic cancer, which is caused by clonal expansion of immature myeloid precursors, leading to bone marrow failure and poor long-term survival, especially in older patients and those with adverse-risk features. Relapse, primarily from chemotherapy-resistant leukemic stem cells (LSCs) in protective niches, remains the leading cause of mortality despite genomic advancements and targeted therapies like FLT3 inhibitors and all-trans retinoic acid for acute promyelocytic leukemia. Conventional antibody-based approaches, such as gemtuzumab ozogamicin, offer benefits but are limited by poor tissue penetration, Fc-mediated off-target effects, toxicity, and high costs, particularly with antigens shared by normal progenitors. Single-domain antibodies (nanobodies), compact (~ 12–15 kDa) scaffolds from camelid heavy-chain antibodies, address these challenges through superior stability, solubility, tissue infiltration, and modular engineering for multivalent/multispecific formats. This review explores AML’s molecular pathogenesis, emphasizing recurrent abnormalities (e.g., NPM1, FLT3, CEBPA mutations) that guide risk stratification and interventions. Diagnostic modalities morphology, flow cytometry, cytogenetics, and next-generation sequencing (NGS) are evaluated for subtype identification and measurable residual disease (MRD) monitoring. Nanobodies excel in positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging of markers like CD33 and AXL, yielding high tumor-to-background ratios in preclinical models, alongside fluorescent conjugates and chromobodies for live-cell visualization. Therapeutic bispecific engagers and CAR-T constructs targeting CD33/CD123 show potent activity against heterogeneous blasts and LSCs. Challenges include antigen variability, rapid clearance, and bone marrow access, mitigated by optimizations like PEGylation. Nanobodies promise precision AML management, enhancing detection, specificity, and relapse prevention through clinical translation.
2025-11-13 | The comprehensive landscape of TTMV::RARA fusiondriven acute myeloid leukemia: from viral integration mechanisms to clinical outcomes.
Acute myeloid leukemia (AML) with TTMV::RARA fusion represents a novel subtype driven by torque teno mini virus (TTMV) integration into the retinoic acid receptor α (RARA) locus, while current understanding of its molecular features and clinical presentation relies predominantly on isolated case observations. Here, we characterize a large and independent cohort (N=25) through integrative analysis of clinical-omics data, uncovering unique features that distinguish it from classic acute promyelocytic leukemia (APL) and other AML subtypes. Our findings reveal that TTMV integrates exclusively within intron 2 of the RARA gene via microhomology-mediated end joining, forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72%, age <18 years) and often presented with extramedullary diseases (24% with myeloid sarcoma, 16% with central nervous system infiltration). Blasts displayed APL-like morphology and immunophenotype but lacked PML::RARA, instead harboring TTMV::RARA with recurrent i(17)(q10) abnormalities (24%). Unsupervised clustering revealed it as a molecularly distinct subgroup. Transcriptomic profiling identified a Wnt-activated/extracellular matrix-dysregulated signature, driving leukemogenesis via dual mechanisms of clonal expansion and metastatic pathways. Despite achieving a 96% complete remission rate with induction therapy, long-term outcomes were significantly inferior, with 2-year event-free survival and relapse-free survival rates of 53.6% and 53.8%, respectively. Hematopoietic stem cell transplantation achieved durable remission in nine of 11 patients, particularly those with extramedullary disease or i(17)(q10) abnormalities. Conclusively, this work establishes TTMV::RARA as a novel AML subtype, highlighting the need for viral screening in APL-like cases and hematopoietic stem cell transplantation prioritization for this subset.
2025-09-09 | Prognostic Value of Molecular and Clinical Features in Patients with NPM1 Gene Mutation in Acute Myeloid Leukemia.
Nucleophosmin 1 (NPM1) mutations represent one of the most frequent genetic alterations in acute myeloid leukemia (AML). However, the prognostic significance of concurrent molecular abnormalities and clinical features in NPM1-mutated AML remains to be fully elucidated. We retrospectively analyzed 73 adult AML patients with NPM1 mutations. Clinical characteristics, molecular features, and treatment outcomes were evaluated. Comprehensive molecular profiling was performed to detect concurrent mutations. Survival analysis included recurrence-free survival (RFS) and overall survival (OS), with multivariate analysis to identify independent prognostic factors. The cohort showed a female predominance (54.8%), with a median age of 53.1 years. FLT3-ITD mutations were detected in 49.3% of patients, followed by DNMT3A (42.5%) and IDH1 (23.3%) mutations. Significant differences across FAB subtypes were observed in blast percentage (p = 0.003), WBC count (p = 0.013), and platelet count (p = 0.004). Multivariate analysis identified elevated WBC count (HR = 1.01, p = 0.008), increased LDH levels (HR = 1.0, p = 0.006), and FLT3-ITD mutations (HR = 2.55, p = 0.007) as independent adverse factors for RFS. For OS, low albumin levels (HR = 0.89, p = 0.017), DNMT3A mutations (HR = 2.49, p = 0.042), and treatment response were significant prognostic factors, while allogeneic hematopoietic stem cell transplantation showed a protective effect (HR = 0.08, p = 0.015). Our findings demonstrate that the clinical outcomes of NPM1-mutated AML are significantly influenced by concurrent molecular mutations and clinical parameters. The presence of FLT3-ITD and DNMT3A mutations, along with specific clinical features, identifies patients with adverse prognosis who might benefit from more intensive therapeutic strategies, including allogeneic transplantation.
2025-06-25 | Protective effects for HLA-B*40:01 and C*03:04 in NPM1-mutated AML: result of a large HLA association study.
Mutations in the nucleophosmin 1 gene (NPM1) are common and recurrent molecular abnormalities in acute myeloid leukemia (AML). NPM1 mutations are considered to be positive prognostic factors. The beneficial effect may be due to immune responses mediated by cytotoxic T cells targeting HLA-presented peptides derived from mutated NPM1 and thereby suppressing mutated NPM1-positive hematopoiesis. While the immunogenicity of these NPM1 peptides has not been demonstrated conclusively, certain HLA-types have been linked to a lower risk of NPM1-mutated AML. In a comprehensive HLA association study at two-field resolution, we compared the proportions of HLA class I alleles between NPM1-mutated (n = 477) and/or DNMT3A-mutated (n = 216) patients with AML and a control group of healthy individuals (n = 51,890). We found HLA-B*40:01 and HLA-C*03:04 to be significantly underrepresented in NPM1-mutated AML compared to the control group (4.0% vs. 10.2%, p < 0.001, and 8.2% vs, 15.9%, p < 0.001, respectively). This might suggest that neoepitopes presented by these HLA alleles trigger T-cell responses. Online epitope prediction tools predict that mutated NPM1-derived peptides bind strongly to B*40:01 and C*03:04. Based on these findings, further studies should confirm the presence and functionality of neoepitope-specific T cells and characterize specific T-cell receptors (TCR). Sequence information might eventually be exploited in immunotherapeutic approaches to treat AML patients with TCR-engineered T cells or bispecific TCR T/NK cell engagers.
2024-02-21 | Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.
oligonucleotides
2024-02-09 | Oncogenic lncRNA FAM215A promotes the malignant cell phenotypes of acute myeloid leukemia (AML) cell lines.
Acute myeloid leukemia (AML) is a form of blood cancer that arise as a result of clonal proliferation of malignant myeloid precursors acquiring genetic abnormalities. Primary resistance to initial treatment and disease recurrence continues to be huge challenge in treating AML. Herein, GSE114868 was analyzed for differentially-expressed lncRNAs between AML patients' mononucleated cells and healthy normal control mononucleated cells and 191 lncRNAs were significantly deregulated in AML patients' mononucleated cells. The correlation between candidate lncRNAs and AML patients' overall survival was analyzed and 6 lncRNAs, including MIR181A1HG, TRAF3IP2-AS1, STARD4-AS1, E2F3-IT1, FAM215A, and HHIP-AS1 were dramatically linked to AML patients' OS. Using a Cox proportional-hazards model, we identified risk factors and found FAM215A as a risk factor for AML patients' prognosis. The expression level of FAM215A showed to be upregulated within blood samples and cells. Genes correlated with FAM215A were correlated to cell division, modulation of cell apoptosis, and modulation of programmed cell death. FAM215A knockdown inhibited AML cell viability, elicited G0/G1-phase arrest of cell cycle, enhanced cell apoptosis, increased proapoptotic Bax and cleaved-caspase3 levels, and decreased antiapoptotic Bcl2. FAM215A overexpression exerted opposite effects on AML cells. Conclusively, FAM215A serves as an oncogenic lncRNA in AML, promoting cell viability, relieving cell cycle arrest, and suppressing cell apoptosis. FAM215A might be un underlying biological prognostic marker and therapeutic target for AML.
2021-06-27 | The contribution of single-cell analysis of acute leukemia in the therapeutic strategy
Abstract After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.
2014-07-09 | Human BDH2, an anti-apoptosis factor, is a novel poor prognostic factor for de novo cytogenetically normal acute myeloid leukemia.
The relevance of recurrent molecular abnormalities in cytogenetically normal (CN) acute myeloid leukemia (AML) was recently acknowledged by the inclusion of molecular markers such as NPM1, FLT3, and CEBPA as a complement to cytogenetic information within both the World Health Organization and the European Leukemia Net classifications. Mitochondrial metabolism is different in cancer and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2, 3-DHBA during enterobactin biosynthesis and participates in 24p3 (LCN2)-mediated iron transport and apoptosis. We observed that BDH2 expression is an independent poor prognostic factor for CN-AML, with an anti-apoptotic role. Patients with high BDH2 expression have relatively shorter overall survival (P = 0.007) and a low complete response rate (P = 0.032). BDH2-knockdown (BDH2-KD) in THP1 and HL60 cells increased the apoptosis rate under reactive oxygen species stimulation. Decrease inducible survivin, a member of the inhibitors of apoptosis family, but not members of the Bcl-2 family, induced apoptosis via a caspase-3-independent pathway upon BDH2-KD. BDH2 is a novel independent poor prognostic marker for CN-AML, with the role of anti-apoptosis, through surviving.
2013-01-16 | Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.
NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation.
gene therapies
2023-01-31 | Mechanisms associated with t(7;12) acute myeloid leukaemia: from genetics to potential treatment targets.
Acute myeloid leukaemia (AML), typically a disease of elderly adults, affects 8 children per million each year, with the highest paediatric incidence in infants aged 0-2 of 18 per million. Recurrent cytogenetic abnormalities contribute to leukaemia pathogenesis and are an important determinant of leukaemia classification. The t(7;12)(q36;p13) translocation is a high-risk AML subtype exclusively associated with infants and represents the second most common abnormality in this age group. Mechanisms of t(7;12) leukaemogenesis remain poorly understood. The translocation relocates the entire MNX1 gene within the ETV6 locus, but a fusion transcript is present in only half of the patients and its significance is unclear. Instead, research has focused on ectopic MNX1 expression, a defining feature of t(7;12) leukaemia, which has nevertheless failed to produce transformation in conventional disease models. Recently, advances in genome editing technologies have made it possible to recreate the t(7;12) rearrangement at the chromosomal level. Together with recent studies of MNX1 involvement using murine in vivo, in vitro, and organoid-based leukaemia models, specific investigation on the biology of t(7;12) can provide new insights into this AML subtype. In this review, we provide a comprehensive up-to-date analysis of the biological features of t(7;12), and discuss recent advances in mechanistic understanding of the disease which may deliver much-needed therapeutic opportunities to a leukaemia of notoriously poor prognosis.
small molecules
2026-09-26 | Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.
Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.
2026-05-15 | TP53-mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition.
TP53-mutated acute myeloid leukemia (AML) represents a particularly aggressive and therapeutically refractory subtype of the disease. While recurrent chromosomal abnormalities such as -5/del(5q), -7/del(7q), and del(17p) are well studied in this context, additional co-occurring events remain less well defined. Using the multidimensional Leucegene dataset (~700 primary AML specimens), we identified and comprehensively characterized a distinct subset of TP53-altered AML marked by recurrent deletions on the short arm of chromosome 3 [del(3p), >20% TP53-mutated cases]. These deletions frequently co-occur with del(5q) and encompass several ribosomal protein genes (RPGs), leading to a global down-regulation of the ribosomal network and reduced protein synthesis. We show that this ribosomopathy-like phenotype is most pronounced in TP53-mutated cases with combined RPG deletions on chromosomes 3p and 5q, suggesting a cooperative oncogenic mechanism. Chemical screening identified HSP90 inhibition as a selective vulnerability in AML with low RPG expression. These findings highlight a previously unappreciated TP53-altered AML subset characterized by converging genomic and translational defects and suggest that ribosomal stress may serve as a therapeutic entry point for targeted intervention of this patient subgroup.
2026-03-30 | Aggressive extramedullary acute myeloid leukaemia masquerading as dental infection with rare t(10:11) translocation and subsequent relapse as leukaemia cutis.
Extramedullary leukaemia, also known as myeloid sarcoma, is a rare manifestation of acute myeloid leukaemia (AML) that typically occurs in conjunction with bone marrow involvement. It is characterized by infiltration of leukemic cells into extramedullary tissues, including the skin, soft tissues, and lymph nodes, where it may present as mass-like or nodular lesions. When associated with high-risk cytogenetic abnormalities, extramedullary disease may exhibit particularly aggressive behaviour and pose substantial diagnostic challenges, especially when it precedes or masks systemic manifestations of AML. A 36-year-old postpartum woman, 6 months following delivery, presented with a 3-month history of progressively enlarging nodules involving the left side of the face. These lesions were initially attributed to a dental infection following extraction of two teeth; however, they persisted and progressed despite appropriate dental treatment. In the weeks preceding this presentation, the patient had developed worsening fatigue, dyspnoea, jaundice, and easy bruising. On examination, there were several firms, non-tender nodules over the left cheek, prominent left cervical lymphadenopathy, scleral icterus, and diffuse ecchymoses. Laboratory results showed pancytopenia with severe anaemia, thrombocytopenia, and neutropenia, elevated liver enzymes suggestive of systemic involvement. The initial differential diagnosis included chronic infection, granulomatous disease, and hematologic malignancy. Following this, imaging showed multifocal facial soft-tissue masses and extensive cervical lymphadenopathy. Core biopsy of a cheek lesion showed diffuse infiltration by atypical myeloid cells consistent with extramedullary AML with monocytic differentiation, which was confirmed on bone marrow biopsy. Cytogenetic analysis revealed a t(10;11)(p13;q13.3), an additional der (20) t(1;20)(q21;q13.3), and a marker chromosome. Induction chemotherapy with cytarabine and idarubicin was initiated. Following consolidation therapy, the patient developed new cutaneous nodules and plaques several weeks later, and skin biopsy confirmed leukaemia cutis, indicating persistent extramedullary disease. This case illustrates a rare and aggressive presentation of extramedullary AML with monocytic differentiation and high-risk cytogenetics in a young postpartum patient, initially mimicking a localized odontogenic infection. The delayed diagnosis underscores the complexity of recognizing extramedullary leukaemia, particularly when early hematologic abnormalities are subtle or absent. The presence of a t(10;11) translocation and the subsequent development of leukaemia cutis following induction therapy highlight the aggressive biologic behaviour of this disease and reinforce the importance of heightened clinical suspicion, prompt tissue diagnosis, and vigilant surveillance for extramedullary relapse, which may require intensified therapeutic approaches.
2025-09-03 | Ruxolitinib and decitabine plus a busulfan-cyclophosphamide conditioning regimen for relapse prophylaxis in patients with high-risk acute myeloid leukemia or myelodysplastic syndromes.
Relapse remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome-IB (MDS-IB) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib has demonstrated antileukemic activity in vitro, and decitabine has been found to be tolerable when combined with modified busulfan-cyclophosphamide (mBu/Cy) conditioning regimen. Here, we investigated the efficacy of ruxolitinib and decitabine plus a mBu/Cy conditioning regimen (Rux-Dec-mBu/Cy) in reducing relapse in high-risk AML/MDS patients (ClinicalTrials.gov identifier: NCT04582604). This prospective investigational study enrolled 58 patients between May 2020 and July 2023. These patients had either a relapsed/refractory status, remission status with adverse genetic abnormalities or positive measurable residual disease (MRD+) prior to conditioning. Ruxolitinib (days -15 to -1) and decitabine (days -15 to -10) were administered, followed by mBu/Cy conditioning. The outcomes of a historical cohort of 58 patients (matched 1:1) who received mBu/Cy are described for reference. All 58 patients achieved engraftment. With a median follow-up of 967 (464-1597) days, the 2-year cumulative incidence of relapse was 19.0%. The probabilities of 2-year overall survival (OS), disease-free survival (DFS) and graft-versus-host disease-free, relapse-free survival (GRFS) were 70.3%, 70.6% and 65.2%, respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 44.1%. The most common grade ≥3 adverse event was oropharyngeal mucositis (8.6%, n=5). Within 6 months post-transplantation, the cumulative incidence of cytomegalovirus (CMV) reactivation was 34.5%, and that of Epstein-Barr virus (EBV) reactivation was 62.1%. This investigational study revealed that the Rux-Dec-mBu/Cy conditioning was tolerable and reduced relapse in high-risk AML/MDS patients.
2025-02-04 | Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.
cell therapies
2026-03-29 | The diagnostic potential of nanobodies in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a heterogeneous hematologic cancer, which is caused by clonal expansion of immature myeloid precursors, leading to bone marrow failure and poor long-term survival, especially in older patients and those with adverse-risk features. Relapse, primarily from chemotherapy-resistant leukemic stem cells (LSCs) in protective niches, remains the leading cause of mortality despite genomic advancements and targeted therapies like FLT3 inhibitors and all-trans retinoic acid for acute promyelocytic leukemia. Conventional antibody-based approaches, such as gemtuzumab ozogamicin, offer benefits but are limited by poor tissue penetration, Fc-mediated off-target effects, toxicity, and high costs, particularly with antigens shared by normal progenitors. Single-domain antibodies (nanobodies), compact (~ 12–15 kDa) scaffolds from camelid heavy-chain antibodies, address these challenges through superior stability, solubility, tissue infiltration, and modular engineering for multivalent/multispecific formats. This review explores AML’s molecular pathogenesis, emphasizing recurrent abnormalities (e.g., NPM1, FLT3, CEBPA mutations) that guide risk stratification and interventions. Diagnostic modalities morphology, flow cytometry, cytogenetics, and next-generation sequencing (NGS) are evaluated for subtype identification and measurable residual disease (MRD) monitoring. Nanobodies excel in positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging of markers like CD33 and AXL, yielding high tumor-to-background ratios in preclinical models, alongside fluorescent conjugates and chromobodies for live-cell visualization. Therapeutic bispecific engagers and CAR-T constructs targeting CD33/CD123 show potent activity against heterogeneous blasts and LSCs. Challenges include antigen variability, rapid clearance, and bone marrow access, mitigated by optimizations like PEGylation. Nanobodies promise precision AML management, enhancing detection, specificity, and relapse prevention through clinical translation.
2025-11-13 | The comprehensive landscape of TTMV::RARA fusiondriven acute myeloid leukemia: from viral integration mechanisms to clinical outcomes.
Acute myeloid leukemia (AML) with TTMV::RARA fusion represents a novel subtype driven by torque teno mini virus (TTMV) integration into the retinoic acid receptor α (RARA) locus, while current understanding of its molecular features and clinical presentation relies predominantly on isolated case observations. Here, we characterize a large and independent cohort (N=25) through integrative analysis of clinical-omics data, uncovering unique features that distinguish it from classic acute promyelocytic leukemia (APL) and other AML subtypes. Our findings reveal that TTMV integrates exclusively within intron 2 of the RARA gene via microhomology-mediated end joining, forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72%, age <18 years) and often presented with extramedullary diseases (24% with myeloid sarcoma, 16% with central nervous system infiltration). Blasts displayed APL-like morphology and immunophenotype but lacked PML::RARA, instead harboring TTMV::RARA with recurrent i(17)(q10) abnormalities (24%). Unsupervised clustering revealed it as a molecularly distinct subgroup. Transcriptomic profiling identified a Wnt-activated/extracellular matrix-dysregulated signature, driving leukemogenesis via dual mechanisms of clonal expansion and metastatic pathways. Despite achieving a 96% complete remission rate with induction therapy, long-term outcomes were significantly inferior, with 2-year event-free survival and relapse-free survival rates of 53.6% and 53.8%, respectively. Hematopoietic stem cell transplantation achieved durable remission in nine of 11 patients, particularly those with extramedullary disease or i(17)(q10) abnormalities. Conclusively, this work establishes TTMV::RARA as a novel AML subtype, highlighting the need for viral screening in APL-like cases and hematopoietic stem cell transplantation prioritization for this subset.
2025-09-09 | Prognostic Value of Molecular and Clinical Features in Patients with NPM1 Gene Mutation in Acute Myeloid Leukemia.
Nucleophosmin 1 (NPM1) mutations represent one of the most frequent genetic alterations in acute myeloid leukemia (AML). However, the prognostic significance of concurrent molecular abnormalities and clinical features in NPM1-mutated AML remains to be fully elucidated. We retrospectively analyzed 73 adult AML patients with NPM1 mutations. Clinical characteristics, molecular features, and treatment outcomes were evaluated. Comprehensive molecular profiling was performed to detect concurrent mutations. Survival analysis included recurrence-free survival (RFS) and overall survival (OS), with multivariate analysis to identify independent prognostic factors. The cohort showed a female predominance (54.8%), with a median age of 53.1 years. FLT3-ITD mutations were detected in 49.3% of patients, followed by DNMT3A (42.5%) and IDH1 (23.3%) mutations. Significant differences across FAB subtypes were observed in blast percentage (p = 0.003), WBC count (p = 0.013), and platelet count (p = 0.004). Multivariate analysis identified elevated WBC count (HR = 1.01, p = 0.008), increased LDH levels (HR = 1.0, p = 0.006), and FLT3-ITD mutations (HR = 2.55, p = 0.007) as independent adverse factors for RFS. For OS, low albumin levels (HR = 0.89, p = 0.017), DNMT3A mutations (HR = 2.49, p = 0.042), and treatment response were significant prognostic factors, while allogeneic hematopoietic stem cell transplantation showed a protective effect (HR = 0.08, p = 0.015). Our findings demonstrate that the clinical outcomes of NPM1-mutated AML are significantly influenced by concurrent molecular mutations and clinical parameters. The presence of FLT3-ITD and DNMT3A mutations, along with specific clinical features, identifies patients with adverse prognosis who might benefit from more intensive therapeutic strategies, including allogeneic transplantation.
2025-06-25 | Protective effects for HLA-B*40:01 and C*03:04 in NPM1-mutated AML: result of a large HLA association study.
Mutations in the nucleophosmin 1 gene (NPM1) are common and recurrent molecular abnormalities in acute myeloid leukemia (AML). NPM1 mutations are considered to be positive prognostic factors. The beneficial effect may be due to immune responses mediated by cytotoxic T cells targeting HLA-presented peptides derived from mutated NPM1 and thereby suppressing mutated NPM1-positive hematopoiesis. While the immunogenicity of these NPM1 peptides has not been demonstrated conclusively, certain HLA-types have been linked to a lower risk of NPM1-mutated AML. In a comprehensive HLA association study at two-field resolution, we compared the proportions of HLA class I alleles between NPM1-mutated (n = 477) and/or DNMT3A-mutated (n = 216) patients with AML and a control group of healthy individuals (n = 51,890). We found HLA-B*40:01 and HLA-C*03:04 to be significantly underrepresented in NPM1-mutated AML compared to the control group (4.0% vs. 10.2%, p < 0.001, and 8.2% vs, 15.9%, p < 0.001, respectively). This might suggest that neoepitopes presented by these HLA alleles trigger T-cell responses. Online epitope prediction tools predict that mutated NPM1-derived peptides bind strongly to B*40:01 and C*03:04. Based on these findings, further studies should confirm the presence and functionality of neoepitope-specific T cells and characterize specific T-cell receptors (TCR). Sequence information might eventually be exploited in immunotherapeutic approaches to treat AML patients with TCR-engineered T cells or bispecific TCR T/NK cell engagers.
2024-02-21 | Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.
oligonucleotides
2024-02-09 | Oncogenic lncRNA FAM215A promotes the malignant cell phenotypes of acute myeloid leukemia (AML) cell lines.
Acute myeloid leukemia (AML) is a form of blood cancer that arise as a result of clonal proliferation of malignant myeloid precursors acquiring genetic abnormalities. Primary resistance to initial treatment and disease recurrence continues to be huge challenge in treating AML. Herein, GSE114868 was analyzed for differentially-expressed lncRNAs between AML patients' mononucleated cells and healthy normal control mononucleated cells and 191 lncRNAs were significantly deregulated in AML patients' mononucleated cells. The correlation between candidate lncRNAs and AML patients' overall survival was analyzed and 6 lncRNAs, including MIR181A1HG, TRAF3IP2-AS1, STARD4-AS1, E2F3-IT1, FAM215A, and HHIP-AS1 were dramatically linked to AML patients' OS. Using a Cox proportional-hazards model, we identified risk factors and found FAM215A as a risk factor for AML patients' prognosis. The expression level of FAM215A showed to be upregulated within blood samples and cells. Genes correlated with FAM215A were correlated to cell division, modulation of cell apoptosis, and modulation of programmed cell death. FAM215A knockdown inhibited AML cell viability, elicited G0/G1-phase arrest of cell cycle, enhanced cell apoptosis, increased proapoptotic Bax and cleaved-caspase3 levels, and decreased antiapoptotic Bcl2. FAM215A overexpression exerted opposite effects on AML cells. Conclusively, FAM215A serves as an oncogenic lncRNA in AML, promoting cell viability, relieving cell cycle arrest, and suppressing cell apoptosis. FAM215A might be un underlying biological prognostic marker and therapeutic target for AML.
2021-06-27 | The contribution of single-cell analysis of acute leukemia in the therapeutic strategy
Abstract After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.
2014-07-09 | Human BDH2, an anti-apoptosis factor, is a novel poor prognostic factor for de novo cytogenetically normal acute myeloid leukemia.
The relevance of recurrent molecular abnormalities in cytogenetically normal (CN) acute myeloid leukemia (AML) was recently acknowledged by the inclusion of molecular markers such as NPM1, FLT3, and CEBPA as a complement to cytogenetic information within both the World Health Organization and the European Leukemia Net classifications. Mitochondrial metabolism is different in cancer and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2, 3-DHBA during enterobactin biosynthesis and participates in 24p3 (LCN2)-mediated iron transport and apoptosis. We observed that BDH2 expression is an independent poor prognostic factor for CN-AML, with an anti-apoptotic role. Patients with high BDH2 expression have relatively shorter overall survival (P = 0.007) and a low complete response rate (P = 0.032). BDH2-knockdown (BDH2-KD) in THP1 and HL60 cells increased the apoptosis rate under reactive oxygen species stimulation. Decrease inducible survivin, a member of the inhibitors of apoptosis family, but not members of the Bcl-2 family, induced apoptosis via a caspase-3-independent pathway upon BDH2-KD. BDH2 is a novel independent poor prognostic marker for CN-AML, with the role of anti-apoptosis, through surviving.
2013-01-16 | Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.
NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation.
gene therapies
2023-01-31 | Mechanisms associated with t(7;12) acute myeloid leukaemia: from genetics to potential treatment targets.
Acute myeloid leukaemia (AML), typically a disease of elderly adults, affects 8 children per million each year, with the highest paediatric incidence in infants aged 0-2 of 18 per million. Recurrent cytogenetic abnormalities contribute to leukaemia pathogenesis and are an important determinant of leukaemia classification. The t(7;12)(q36;p13) translocation is a high-risk AML subtype exclusively associated with infants and represents the second most common abnormality in this age group. Mechanisms of t(7;12) leukaemogenesis remain poorly understood. The translocation relocates the entire MNX1 gene within the ETV6 locus, but a fusion transcript is present in only half of the patients and its significance is unclear. Instead, research has focused on ectopic MNX1 expression, a defining feature of t(7;12) leukaemia, which has nevertheless failed to produce transformation in conventional disease models. Recently, advances in genome editing technologies have made it possible to recreate the t(7;12) rearrangement at the chromosomal level. Together with recent studies of MNX1 involvement using murine in vivo, in vitro, and organoid-based leukaemia models, specific investigation on the biology of t(7;12) can provide new insights into this AML subtype. In this review, we provide a comprehensive up-to-date analysis of the biological features of t(7;12), and discuss recent advances in mechanistic understanding of the disease which may deliver much-needed therapeutic opportunities to a leukaemia of notoriously poor prognosis.
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Drug Discovery Landscape
1 orphan drug designation for Acute myeloid leukemia with recurrent genetic anomaly.
1 orphan drug designation for Acute myeloid leukemia with recurrent genetic anomaly.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
FTV1+GDP-fucose | small molecules | FDA | America Stem Cell, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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