RARE DISEASE
Myeloproliferative neoplasm
Myeloproliferative neoplasm
Myeloproliferative neoplasm
Synonyms: MPD, MPN, Myeloproliferative disorder
Synonyms: MPD, MPN, Myeloproliferative disorder
Synonyms: MPD, MPN, Myeloproliferative disorder
Drug discovery
3
drugs
With orphan designations
Overview
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by excessive production of mature blood cells, often driven by mutations in JAK2, CALR, or MPL genes. They include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), with rare progression to acute myeloid leukemia (AML) [1][2][7]. Chronic inflammation and symptom burden are hallmarks, necessitating tailored therapies [5][9].
Therapies
Symptom control: Phlebotomy (PV), ruxolitinib (JAK1/2 inhibitor), hydroxyurea, interferon-α [1][2][8].
Curative: Allogeneic stem cell transplant (limited by age/comorbidities) [3][17].
Emerging: Imetelstat (telomerase inhibitor), CALR-targeted vaccines, and combination therapies in trials [3][8][16].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,193 drug discovery papers about Myeloproliferative neoplasm, with 6 first-in-class and 46 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,193 drug discovery papers about Myeloproliferative neoplasm, with 6 first-in-class and 46 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Recent Advances in Chronic Myeloid Leukaemia (CML): Emerging Molecular and Immunotherapeutic Targets.
Chronic myeloid leukaemia (CML), a distinct myeloproliferative neoplasm, results from the malignant reprogramming of haematopoietic stem cells (HSCs) into leukaemia stem cells (LSCs), primarily driven by breakpoint cluster region and Abelson (BCR-ABL1) fusion oncogene. Although the advent of tyrosine kinase inhibitors (TKIs) has significantly transformed clinical management, leading to improved patient survival and quality of life, sustained treatment-free remission (TFR) remains achievable in only a minority of patients. This limitation is largely attributable to the persistence of LSCs and the development of resistance mechanisms. Emerging evidence indicates that LSCs evade TKI-induced apoptosis through aberrant expression of specific cell-surface markers, dysregulated intracellular signalling pathways, and extensive epigenetic alterations. This review examines recent advancements in CML therapy, with a focus on these novel therapeutic targets. It highlights the pivotal role of LSCs in disease progression and relapse, evaluates potential molecular and epigenetic regulators as new targets for intervention, and supports the development of combination treatment strategies to improve TFR rates and move towards curative outcomes.
2026-09-27 | Reassessing the clinical value of momelotinib in myelofibrosis: An ESMO-MCBS:H-based appraisal of SIMPLIFY-1 and MOMENTUM.
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, systemic symptoms, and anemia, the latter being strongly associated with poor survival and reduced quality of life. Current Janus kinase (JAK) inhibitors improve symptoms and spleen size but often exacerbate anemia, leaving a significant unmet clinical need. Momelotinib, a JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor, has been proposed to address both splenomegaly and anemia through hepcidin suppression. This study critically evaluates the clinical benefit of momelotinib using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H), focusing on the phase 3 trials SIMPLIFY-1 and MOMENTUM. In SIMPLIFY-1, momelotinib demonstrated non-inferiority to ruxolitinib in terms of spleen volume reduction (SVR35 26.5% vs 29.0%) and did not evaluated quality of life as a prespecified outcome, resulting in an ESMO-MCBS:H score indicating no evaluable benefit (NEB). In contrast, in MOMENTUM, conducted in symptomatic, anemic patients previously treated with JAK inhibitors, momelotinib was superior to danazol for MFSAF total symptom score response (≥50% reduction from baseline 25% vs 9%). As no improvement in global health status was observed, MOMENTUM was scored as Grade 1. Interpretation of hematologic benefits remains limited by trial design, as the anemia related outcomes were not primary endpoints and studies were not powered to robustly assess them. Furthermore, the negative SIMPLIFY-2 trial underscores uncertainty in pretreated populations. In conclusion, momelotinib demonstrates a differentiated clinical profile with consistent spleen control and potential hematologic benefits, particularly in anemic patients. However, superiority over other improved JAK inhibitors has not been demonstrated in the pivotal phase 3 trials evaluated. Future trials incorporating anemia-focused primary endpoints and biomarker stratification are warranted to better define its role in myelofibrosis management.
2026-09-26 | The Roles of Genetic and Epigenetic Abnormalities in Essential Thrombocythemia.
Essential thrombocythemia (ET) is a Ph(-) myeloproliferative neoplasm characterized by elevated platelet counts. Patients most often have one of the three following driver mutations: JAK2, MPL, or CALR. However, these mutations are not detected in approximately 10-15% of patients, who are thus referred to as "triple-negative" (TN). Background/Objectives: In recent years, there have been breakthroughs in the genetic diagnosis of hematological diseases and progress in understanding their epigenetic basis. Aim: This study aimed to review the available literature and systematize the current knowledge on the molecular abnormalities in essential thrombocythemia. Particular attention was paid to the impacts of genetic mutations and epigenetic changes-such as abnormalities in non-coding RNA expression, DNA methylation, and histone modifications-on disease development and their clinical significance in patients with essential thrombocythemia. The most important publications on genetic and epigenetic mechanisms in essential thrombocythemia were reviewed and summarized. Methods: A review of the available literature was conducted using selected online databases. Publications from 2003 to 2026 were considered, covering the diagnosis and classification criteria for essential thrombocythemia, its genetic and epigenetic basis, and the associated impacts on the disease course. Conclusions: Although understanding the precise roles of genetic and epigenetic abnormalities in essential thrombocythemia remains challenging, they offer many opportunities for use as new diagnostic biomarkers and for the development of novel targeted treatment options. Further research is needed to better understand the genetic and epigenetic changes occurring in ET.
2026-09-25 | ATM mutations in myelodysplastic neoplasms, acute myeloid leukemia, and myeloproliferative neoplasms: a systematic review.
Ataxia Telangiectasia Mutated (ATM), a central kinase in the DNA damage response, is recurrently altered across these disorders, including myelodysplastic neoplasms (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN), yet its clinical significance remains underrecognized. We conducted a PROSPERO-registered systematic review (CRD420251142673) to evaluate the prognostic and biological impact of ATM alterations in MDS, AML, and MPN. Ten studies met inclusion criteria. In MDS, ATM alterations showed consistent downregulation, hypermethylation, and a predominance of oncogenic missense mutations, with methylation significantly enriched in cases progressing to AML. In AML, reduced ATM gene expression, often driven by miR-100 or miR-181a, was associated with increased blast proliferation, while the ATM genetic variant rs3092856 correlated with chemoresistance and inferior survival. Evidence in MPN/CML, although limited, suggests that ATM polymorphisms, such as rs228593, rs3092856 (C4138T), -5144A>T (rs228589), c.5753G>C, c.346A>G, c.4060C>A, and the germline variant L2307F, contribute to disease susceptibility and adverse prognostic stratification. Collectively, current evidence supports ATM alterations as clinically relevant biomarkers in myeloid malignancies, although their functional role in disease pathogenesis remains incompletely understood.. Rather than establishing ATM merely as a prognostic marker, future efforts should prioritize the characterization of ATM-related therapeutic vulnerabilities and integrate ATM status into treatment-oriented molecular panels to guide precision-based interventions in myeloid diseases.
2026-09-24 | Dual-Driver Myeloproliferative Neoplasm: Concurrent p190 BCR::ABL1 CML and JAK2 V617F Mutation: A Case Report and Literature Review.
The concurrent occurrence of BCR::ABL1 rearrangement and JAK2 V617F mutation is an exceptionally rare phenomenon, with reported frequencies of 0.2%-2.5% in tested myeloproliferative neoplasm (MPN) cohorts and an estimated overall rate of approximately 0.4% in patients screened for both alterations. These molecular drivers are generally considered mutually exclusive, as BCR::ABL1 defines Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), while JAK2 V617F characterizes Ph-negative MPNs. We report a male patient in his 50s with a previously detected JAK2 V617F mutation, initially managed as essential thrombocythemia, who later presented with leukocytosis, macrocytic anemia, thrombocytopenia, and absolute monocytosis. Bone marrow demonstrated marked myeloid hyperplasia with atypical megakaryocytes, comprising scattered dwarf forms together with larger forms with "cloud-like" nuclei and focal reticulin fibrosis (MF-1). These findings, together with the known JAK2 V617F mutation, prompted targeted molecular investigation. High-sensitivity RT-PCR confirmed an isolated e1a2 (p190) BCR::ABL1 transcript, the minor breakpoint cluster region isoform occurring in only 1%-2% of CML cases, with the complete absence of the p210 isoform, alongside a concurrent JAK2 V617F mutation (allele burden 16%). Standard p210-focused quantitative assays would have produced a false-negative result in this case. The patient received first-line asciminib and was subsequently transitioned to dasatinib, with the BCR::ABL1/ABL1 ratio declining from 88.5% at diagnosis to 0.79% at most recent assessment. This case highlights the critical importance of integrated morphologic, cytogenetic, and molecular evaluation in atypical MPN presentations. The admixed megakaryocytic atypia superimposed on myeloid hyperplasia reflected the coexistence of two drivers. Comprehensive profiling, including high-sensitivity RT-PCR capable of detecting the p190 isoform and concurrent JAK2 testing, is essential for accurate diagnosis, prognostication, and therapy selection in these rare dual-driver cases.
cell therapies
2026-07-27 | Impact of High-Risk Mutations and Treatment Intensity in Accelerated-Phase Blast-Phase MPN Without Adverse-Risk Karyotype and TP53.
The prognostic significance of myelodysplasia-related gene mutations (MDS-RGMs), defined by the ELN 2022 classification and Mutation-Enhanced International Prognostic Score System high-risk mutations (MIPSS70-HRM), in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs) remains unclear. We conducted a retrospective study of 101 AP/BP MPN patients with intermediate-risk cytogenetics, excluding TP53 mutations and adverse-risk karyotypes. We evaluated whether MDS-RGM or MIPSS70-HRM predicted treatment response, overall survival (OS), or disease-free survival (DFS) and whether treatment intensity affected OS. Patients included AP (29.7%) and BP (70.3%), with 55% receiving intensive therapy. Allogeneic stem cell transplant (ASCT) significantly improved OS (HR 0.31, 95% CI 0.19-0.50; p < 0.0001), as did AP versus BP at transformation (HR: 0.43, 95% CI 0.26-0.73; p = 0.0016). Among patients ≤ 70 years with ECOG 0-1 (N = 77), ASCT and reversion to chronic-phase MPN (cMPN) were associated with longer OS (p < 0.0001 and p = 0.0475). Treatment intensity alone did not significantly affect OS (p = 0.1991).
2026-06-29 | Thrombocytapheresis as a Bridge Intervention in JAK2-Mutant Myeloproliferative Neoplasm Complicated by Acquired von Willebrand Disease: A Case Report.
Acquired von Willebrand disease (AvWD) in myeloproliferative neoplasms with extreme thrombocytosis causes paradoxical bleeding due to the mechanism of adsorption and ADAMTS13-mediated proteolysis of high-molecular-weight von Willebrand factor (vWF) multimers. When first-line cytoreductive therapy fails due to intolerance or nonadherence, rapid alternatives are limited. We describe a 74-year-old woman with JAK2V617F-mutated myeloproliferative neoplasm and hydroxyurea intolerance who presented with active mucosal bleeding and a platelet count of 952 000/μL. vWF antigen (vWF:Ag) was 0.37 IU/mL (reference range: 0.50-2.00 IU/mL), and vWF Ristocetin Cofactor activity (vWF:RCo) was 0.21 IU/mL (activity/antigen ratio 0.57; reference range 0.7-1.3), consistent with AvWD. A single thrombocytapheresis session on the Fresenius COM.TEC platform reduced the platelet count to 277 000/μL, with prompt cessation of bleeding. Repeat testing at 24 h showed improvement in vWF:RCo to 0.48 IU/mL (ratio 0.68), which likely reflects restoration of functional high-molecular-weight multimers. In this single case, thrombocytapheresis provided rapid and effective platelet reduction for AvWD secondary to myeloproliferative neoplasms when pharmacological cytoreduction is inadequate.
2026-05-22 | The Two-Step Allogeneic Stem Cell Transplant Is Associated with Excellent Engraftment, Improved Survival and Low Nonrelapse Mortality in Patients with Myelofibrosis.
Myelofibrosis is a chronic myeloproliferative disorder primarily affecting older adults, and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. However, HSCT for myelofibrosis presents significant challenges, including high nonrelapse mortality (NRM) and an increased risk of graft failure. In this 20-year retrospective study, we evaluated outcomes for 32 myelofibrosis patients who underwent HSCT at our institution, with particular focus on a two-step transplant approach designed to optimize T-cell dosing by separating the lymphoid and myeloid graft components, with cyclophosphamide administered after the lymphoid infusion and before infusion of CD34-selected stem cells. Eighteen patients underwent transplantation using the two-step approach and demonstrated favorable outcomes, with 1-year and 5-year overall survival (OS) rates of 83% and 68%, respectively. NRM was reduced, with rates of 17% at 1 year and 23% at 5 years. Engraftment was robust, with median neutrophil and platelet recovery at 12 and 19 days, respectively, and a low graft failure rate of 5.9% despite the predominant use of reduced-intensity conditioning and haploidentical donors, compared with 17.5% graft failure among patients receiving a traditional one-step transplant. Across the entire cohort, OS was 66% at 1 year and 54% at 5 years, respectively, with NRM rates of 34% and 42% at 5 years, respectively. The cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was 17% each. These findings suggest that the two-step transplant platform is a viable and effective strategy for improving HSCT outcomes in myelofibrosis, providing lower NRM and favorable engraftment profiles. Further studies are warranted to validate these results and refine HSCT protocols to reduce transplant-related mortality and improve long-term survival in patients with myelofibrosis.
2026-05-13 | Prospects of Chimeric Antigen Receptor T-Cell Therapy in Myelofibrosis: From Immunopathogenesis to Therapeutic Strategies.
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4-CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification.
2026-04-26 | Acute myeloid leukemia after myeloproliferative neoplasms: Real-world outcomes in the new treatment era in the United States.
Progression to acute myeloid leukemia (AML) is a rare complication of myeloproliferative neoplasms (MPNs) with limited treatment options and median overall survival (OS) of 3-6 months. The treatment of AML has been revolutionized in recent years with the introduction of novel targeted therapies including the BCL2 inhibitor venetoclax (VEN). However, evidence regarding outcomes in patients with post-MPN AML remains limited. To evaluate the impact of novel therapies on the outcomes of patients with post-MPN AML, the authors conducted a retrospective analysis of 392 patients who were diagnosed with post-MPN AML during 2014-2024 in the United States and were included in the Flatiron Health Research Database. Although the proportion of patients treated with lower-intensity therapies (LIT) including VEN in combination with hypomethylating agents increased over time, OS was very similar among patients diagnosed before and after VEN approval (median OS, 7.1 [95% confidence interval (CI), 5.7-9.5] months vs. 7.6 [95% CI, 5.8-10.1] months; p = .39). Only 15% of post-MPN AML patients underwent an allogeneic hematopoietic cell transplant (allo-HCT). Those who received allo-HCT experienced better OS than patients who did not receive allo-HCT (median OS, 20.5 [95% CI, 15.4-36.2] months vs. 5.8 [95% CI, 5.0-6.8] months; p < .01). Although patients treated with intensive chemotherapy (IC) had longer OS than those treated with LIT (hazard ratio, 1.95; 95% CI, 1.12-3.41; p = .02), patients receiving IC and LIT as a bridge to allo-HCT had comparable OS (p = .37). This study highlights allo-HCT as the only potentially curative option with both IC and LIT serving as effective bridging therapies.
proteins
2026-09-18 | Molecular Response, Event-Free Survival, and Treatment-Free Remission in Myeloproliferative Neoplasms: Update and Review with Insights from MPN Asia 2026.
Therapeutic goals in BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are evolving to include biologically anchored measures of disease modification with control of blood counts, splenomegaly, and symptoms. Disease modification endpoints and their linkage to survival in MPNs were central to the framework of MPN Asia 2026, which took place in Seoul. This review summarizes key themes from MPN Asia 2026 and relevant recent literature, examining the evolving roles of molecular response and long-term clinical benefits within a broader disease-modification framework across polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Clinical trials with ropeginterferon alfa-2b were central to the discussions given these studies have contributed to the evolving paradigm of disease modification in MPNs, underscoring the importance of molecular response and event-free survival (EFS) in MPN management. In PV, ropeginterferon alfa-2b treatment provides a clinical model linking durable hematologic control and deep JAK2V617F variant allele frequency (VAF) reduction with improved long-term outcomes such as EFS, and prospective treatment-discontinuation strategies. Data from Europe and Asia supports the importance of early disease control, adequate interferon exposure, and longitudinal molecular monitoring. In ET, randomized data with ropeginterferon alfa-2b and emerging new treatment approaches such as lysine-specific demethylase 1 inhibition and mutant CALR-directed therapy are incorporating molecular endpoints into clinical development. However, the association between VAF reduction and thrombosis prevention, disease modification, EFS, and treatment-free remission (TFR) need to be elucidated. In MF, molecular profiling is already integral to prognostication and treatment selection, and disease modification assessment will likely require endpoints encompassing more than symptoms and spleen response, such as anemia response, bone marrow fibrosis change, clonal evolution, patient-reported outcomes, and importantly progression-free and overall survival. Molecular response, clonal suppression, prevention of vascular and progression events, survival outcomes such as EFS and TFR play increasingly important roles in MPN management.
2026-09-16 | Type 1 interferon perturbates clonal competition by reshaping human blood development.
Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.
2026-09-01 | Efficacy and Safety of Ropeginterferon Alfa-2b in Pregnant Women With Myeloproliferative Neoplasms: Case Series of Three Subtypes and Review.
Managing myeloproliferative neoplasms (MPNs) during pregnancy is challenging due to increased thrombotic risk and limited cytoreductive options. Ropeginterferon alfa-2b (ropeginterferon), a long-acting mono-pegylated interferon, has limited data in this setting. We report a Korean multicenter case series of four pregnancies across MPN subtypes, including prefibrotic/early primary myelofibrosis, essential thrombocythemia, and polycythemia vera. Ropeginterferon was used during pregnancy or prior to conception (250-500 μg every 2-12 weeks) with aspirin and/or low-molecular-weight heparin. Hematologic responses were sustained throughout pregnancy without treatment-limiting adverse events. All pregnancies resulted in live births without major maternal or neonatal complications. Within the limits of a small retrospective series, ropeginterferon appeared to be a feasible cytoreductive option in these MPN pregnancies, including pre-conception and intra-pregnancy use; these preliminary observations warrant confirmation in larger prospective studies.
2026-08-26 | Neutrophil-to-lymphocyte ratio as a gene-specific biomarker of JAK2-driven inflammation across CHIP and myeloproliferative neoplasms.
The neutrophil-to-lymphocyte ratio (NLR) has emerged as a mechanistically informative biomarker in clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPNs), although its clinical utility is strongly mutation dependent. NLR is markedly elevated in JAK2V617F-mutated CHIP and MPNs, reflecting neutrophil-driven myeloproliferation, whereas it remains largely unchanged in TET2, DNMT3A, and ASXL1 mutations despite substantial IL-1β- and IL-6-mediated inflammation. This apparent paradox highlights distinct inflammatory programs generated by different driver mutations, with JAK2 promoting neutrophilia and epigenetic mutations primarily activating macrophage-mediated innate immunity. In polycythemia vera, elevated NLR independently predicts thrombosis, myelofibrotic progression, and mortality. Similar prognostic value has been reported in essential thrombocythemia and myelofibrosis, particularly among patients with JAK2 mutations. Beyond risk stratification, NLR also functions as a pharmacodynamic biomarker. During treatment with ropeginterferon alfa-2b, reductions in NLR parallel decreases in JAK2V617F allele burden, whereas persistent NLR elevation during hydroxyurea therapy identifies patients at higher risk of thrombosis and adverse outcomes. Conversely, the CANTOS trial demonstrates that patients with TET2-mutated CHIP derived marked cardiovascular benefit from IL-1β inhibition despite NLR providing limited biological information, underscoring the need for complementary biomarkers in non-JAK2 CHIP. This review integrates mechanistic, clinical, and therapeutic evidence supporting mutation-specific inflammatory biomarkers and proposes NLR-guided strategies for risk assessment, treatment monitoring, and precision management in MPNs and CHIP.
2026-06-26 | A Hidden Driver Mutation in Myeloproliferative Neoplasms: SH2B3 and Diagnostic Implications and Response to Ropeginterferon Alfa-2b.
Myeloproliferative neoplasms (MPNs) are commonly linked to driver mutations in the JAK2, MPL, and CALR genes. In contrast, SH2B3 (LNK) mutations are uncommon and remain an under-characterized contributor to dysregulated JAK-STAT signaling. The clinical features and treatment responsiveness of SH2B3-mutated MPNs are not well defined, and data on outcomes with ropeginterferon alfa-2b in this molecular subgroup are limited. We report a 75-year-old man who presented for evaluation of headache, generalized bone pain, and night sweats and was found to have abnormal blood counts including persistent leukocytosis, erythrocytosis, and thrombocytosis. Prior molecular testing was negative for JAK2, MPL, and CALR mutations. Bone marrow examination showed hypercellularity with panmyelosis, mild megakaryocytic atypia, and WHO grade 1 reticulin fibrosis. Hematologic next-generation sequencing identified a pathogenic SH2B3 c.1481C>G (p.Ser494*) nonsense mutation, predicted to result in a loss of SH2B3's C-terminal regulatory domain. Given the tri-lineage cytoses and marrow findings, a diagnosis of SH2B3-mutated MPN was established. He was started on ropeginterferon alfa-2b, resulting in resolution of his symptoms and complete hematologic response (WBC ≤ 10 × 103/μL, Hct ≤ 45%, and PLT ≤ 400 × 103/μL) within 12 weeks, without the need for phlebotomy or treatment-limiting adverse effects. This case underscores the clinical significance of SH2B3 mutations as a driver of triple-negative MPNs and supports their inclusion in molecular evaluation when classical mutations are absent. The favorable clinical and hematologic response to ropeginterferon alfa-2b suggests that interferon-based therapy may be effective in SH2B3-mutated MPNs.
antibodies
2026-08-19 | Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.
Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR-MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.
2026-06-28 | Beyond the JAK2 mutation: The inflammasome, clonal stability, and the thrombotic niche in myeloproliferative neoplasms.
Philadelphia-negative myeloproliferative neoplasms (MPNs) carry a disproportionate thrombotic burden that cannot be explained by conventional cardiovascular risk factors or blood count parameters alone. This review synthesizes emerging evidence positioning MPN-associated thrombosis as a distinct pathobiologic entity, clonal thrombo-inflammation, driven by the convergence of somatic mutations and innate immune activation. We examine the continuum from clonal hematopoiesis of indeterminate potential (CHIP) to overt MPN, highlighting how Janus kinase 2 (JAK2)V617F and other driver mutations reprogram myeloid cells toward hyperinflammatory phenotypes. A recurring mechanistic theme is NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and interleukin-1 family signaling, which may create a feed-forward loop in which mutant clones amplify inflammatory circuits that, in turn, may enhance clonal fitness and contribute to thrombogenicity across multiple cellular compartments. We propose the 'thrombotic niche' as a conceptual, multi-compartment model encompassing mutant hematopoietic stem cells, hyperinflammatory myeloid effectors, hyperreactive platelets, platelet-leukocyte aggregates, and activated endothelium, but it remains a hypothesis-generating framework that lacks direct prospective clinical validation. Current cytoreductive strategies inadequately address this underlying biology, leaving substantial residual vascular risk. Emerging anti-inflammatory and anti-clonal strategies targeting interleukin-1 beta (IL-1β) (canakinumab), mutant-selective JAK2 inhibition, NLRP3 inflammasome blockade, and P-selectin-mediated adhesion are biologically plausible, but their ability to reduce thrombotic events in MPN remains unproven and should be viewed as hypothesis-generating rather than established clinical benefit. We conclude by outlining a translational research agenda integrating inflammation-aware risk stratification, niche-directed imaging, and spatial multi-omics to guide precision anti-inflammatory interventions in MPN.
2026-06-27 | Neutrophil extracellular traps in thrombosis of hematologic malignancies: Underlying mechanisms and therapeutic opportunities (Review).
Patients with cancer, particularly those diagnosed with hematological malignancies, exhibit thrombus incidence rates that exceed those observed in the general population by a substantial margin, and this elevated risk is associated with worse clinical outcomes. Neutrophil extracellular traps (NETs), which are web‑like structures released by neutrophils as part of their innate immune repertoire, drive coagulation and vascular occlusion by supplying a physical scaffold, recruiting procoagulant factors, and cleaving tissue factor pathway inhibitors. In hematological malignancies, emerging evidence points to NET overproduction and dysregulation as key drivers of thrombosis, representing a previously underappreciated mechanistic axis. The present review focuses on the molecular mechanisms by which NETs promote thrombosis, specifically on thrombosis associated with hematological malignancies (such as myeloproliferative neoplasm, acute myeloid leukemia, Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia), and also explores the clinical translation potential of NET‑related therapies. The present study offers a potential basis for refining current approaches to coagulation risk reduction in patients with hematological malignancies.
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-04-20 | From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms.
This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.
other
2026-02-10 | The Role and Impact of Non-driver Gene Mutations in Myelofibrosis.
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis and potential progression to a blast phase. This review provides a comprehensive overview of the current molecular landscape of MF beyond canonical driver mutations (JAK2, MPL or CALR), emphasizing insights gained from murine models that served as valuable tools for understanding disease mechanisms. High-throughput next-generation sequencing (NGS) has markedly enhanced our understanding of the molecular basis of MF, identifying numerous mutations beyond the canonical driver genes JAK2, MPL, and CALR, which are present in about 80% of patients. Additional mutations affect genes involved in DNA methylation (TET2, DNMT3A, IDH1, IDH2), histone modification (ASXL1, EZH2), mRNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), signaling pathways (CBL, NRAS, KRAS), and key transcription factors (RUNX1, NFE2, TP53). The presence and combination of these alterations influence clinical presentation, prognosis, and therapeutic response. This review offers an updated synthesis of the evolving molecular landscape of MF, highlighting how the intricate interplay among genetic alterations has deepened our understanding of disease heterogeneity, allowing refined risk stratification and therapeutic planning. Advances emerging from molecular research and experimental models are progressively translating into clinical practice, promoting more personalized and targeted approaches to the management of MF.
2026-01-08 | Targeting the JAK2V617F mutant hematopoietic microenvironment in myeloproliferative neoplasm
The acquired JAK2V617F mutation is predominantly detected in hematopoietic stem cells(HSCs), leading to myeloproliferative neoplasms(MPN). Emerging evidence shows that JAK2V617F bearing cells remodel their microenvironment by dysregulating cytokines, and altering adhesion molecules, with histopathological changes in the spleen and liver that influence thrombosis and disease progression. However, how JAK2V617F bearing cells interact with and modify niche factors to promote MPN progression remains insufficiently defined and represents an important therapeutic opportunity. This review focuses on the effect of mutant HSCs on the BM niche, emphasizing key signaling pathways such as IL-β1, TPO/MPL, TGF-β1, VEGF, CXCR4/CXCL12, and altered metabolism. Understanding these dysregulated interactions provides a rationale for therapies that directly target the niche components. Current therapies, including JAK inhibitors, partially address symptoms but are limited by resistance and off-target effects, whereas emerging niche-directed strategies such as such as CXCR4 antagonists, TGF-β1 blockers and metabolic modulators, may restore normal hematopoiesis and overcome ruxolitinib resistance. Therefore, understanding and modulating these HSC-niche interactions advances a path toward durable and transformative therapies for MPNs.
2025-12-19 | Genome editing for treatment of JAK2 V617F-driven myeloproliferative neoplasms
Abstract JAK2 V617F is a common haematological driver mutation and underlies most cases of myeloproliferative neoplasms (MPNs). Reducing variant allele frequency (VAF) is an important treatment goal, but no current treatment modalities fully and specifically inhibit mutant signalling. Thus, the consequences of V617F inactivation are unclear, including whether selective inhibition of V617F signalling will eradicate mutant cells due to oncogene addiction. Here, we describe an allele-selective CRISPR-Cas genome editing strategy that achieves selective and efficient JAK2 V617F inactivation in patient stem and progenitor cells. We show that JAK2 V617F heterozygous cells are not oncogene addicted and maintain viability and differentiation potential upon loss of their mutant allele. In contrast, homozygous mutant cells are eradicated upon deletion of both mutant alleles. Across in vitro , organoid, xenotransplantation and single-cell assays, selective deletion of V617F alleles reverts MPN hallmarks including erythroid clonogenicity, inflammatory gene expression signatures, as well as myelofibrosis and splenomegaly phenotypes in an in vivo xenograft model. Collectively, our results show that is it possible to revert heterozygous JAK2 V617F mutant cells to a normal phenotype and suggest that ex vivo genome editing of stem and progenitor cells may be a viable treatment option to achieve rapid and deep reductions in VAF.
2025-10-08 | ALPHA-TOCOPHEROL AND G-CSF CHANGE EXPRESSION OF GENES ASSOCIATED WITH DIFFERENTIATION OF K562 CHRONIC MYELOID LEUKEMIA CELLS DOWNREGULATING EMT-ASSOCIATED STEMNESS BIOMARKERS.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a block of myeloid differentiation, finally resulting in the uncontrolled expansion of CML stem cells in a phase of blast crisis of the disease. Tyrosine kinase inhibitors (TKI) are effective in delaying CML progression for a long time. Nevertheless, CML cells become resistant to TKI over time. Therefore, the search for alternative and complementary therapies, including differentiation therapy, is currently in the limelight. The aim of the study was to explore the differentiation potential of alpha-tocopherol and granulocyte-colony stimulating factor (G-CSF) by analyzing the gene expression of several factors critical for myeloid differentiation of K562 CML cells, as well as some key leukemic stemness transcription factors. The mRNA expression of C/EBPα (CCAAT/enhancer binding protein alpha), neutrophil-granulocytic factor TNAP (tissue non-specific alkaline phosphatase), E-cadherin, SNAIL, OCT4, and PLAP (placental-like alkaline phosphatase) was studied by qRT-PCR in K562 cells exposed to alpha-tocopherol or G-CSF. K562 cell exposure to alpha-tocopherol or G-CSF resulted in the CEBPB, CDH1, and ALPL gene upregulation. At the same time, down-regulation of EMT-associated markers SNAIL, PLAP, and OCT4 (SNAI1, ALPP, and POU5F1 genes) was demonstrated. The inverse relationship between expression of the genes of leukemic stemness cell markers SNAIL, OCT4, and PLAP and the genes of myeloid differentiation markers C/EBPα, TNAP, and E-cadherin in K562 cells exposed to alpha-tocopherol or G-CSF suggests the activation of the molecular pattern of myeloid differentiation in this setting.
2025-09-18 | Statins enhance the efficacy of pegylated interferon-alfa2 in Philadelphia-negative chronic myeloproliferative neoplasms.
Chronic inflammation may be a key driving force in the development and progression of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Statins, commonly used to lower cholesterol, also possess antiproliferative, proapoptotic, and anti-inflammatory properties that may be beneficial in the treatment of patients with MPN. This retrospective cohort study investigated whether statin use, in addition to standard cytoreductive therapy, shortens the time required to achieve hematological and molecular responses, while allowing for lower cytoreductive drug dosages. A total of 129 patients were included, with 53 receiving statins from diagnosis. The study found that statin users achieved complete hematological response (CHR) significantly faster than nonusers (median time: 8 vs 18 months; hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.4-3.1; P = .0003). Among patients treated with pegylated interferon-alfa2 (IFN-α2), the CHR rate was 97% in statin users vs 83% in nonusers (HR, 2.5; 95% CI, 1.5-3.9; P = .0004), and a higher proportion of statin users sustained CHR throughout follow-up. Additionally, IFN-treated statin users received a significantly lower mean dose of IFN-α2. A dose-response relationship was observed, with higher statin intensity associated with an increase of CHR. Furthermore, statin use was significantly associated with achieving a partial molecular response among IFN-α2-treated patients (HR, 2.6; 95% CI, 1.1-6.0; P = .029). No significant association was observed in hydroxyurea (HU)-treated patients. These findings suggest that statins may enhance the efficacy of IFN-α2 in patients with MPN, while their benefit in HU-treated patients remains unclear. Prospective studies are warranted to further explore the therapeutic potential of statins in MPNs.
small molecules
2026-09-30 | Recent Advances in Chronic Myeloid Leukaemia (CML): Emerging Molecular and Immunotherapeutic Targets.
Chronic myeloid leukaemia (CML), a distinct myeloproliferative neoplasm, results from the malignant reprogramming of haematopoietic stem cells (HSCs) into leukaemia stem cells (LSCs), primarily driven by breakpoint cluster region and Abelson (BCR-ABL1) fusion oncogene. Although the advent of tyrosine kinase inhibitors (TKIs) has significantly transformed clinical management, leading to improved patient survival and quality of life, sustained treatment-free remission (TFR) remains achievable in only a minority of patients. This limitation is largely attributable to the persistence of LSCs and the development of resistance mechanisms. Emerging evidence indicates that LSCs evade TKI-induced apoptosis through aberrant expression of specific cell-surface markers, dysregulated intracellular signalling pathways, and extensive epigenetic alterations. This review examines recent advancements in CML therapy, with a focus on these novel therapeutic targets. It highlights the pivotal role of LSCs in disease progression and relapse, evaluates potential molecular and epigenetic regulators as new targets for intervention, and supports the development of combination treatment strategies to improve TFR rates and move towards curative outcomes.
2026-09-27 | Reassessing the clinical value of momelotinib in myelofibrosis: An ESMO-MCBS:H-based appraisal of SIMPLIFY-1 and MOMENTUM.
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, systemic symptoms, and anemia, the latter being strongly associated with poor survival and reduced quality of life. Current Janus kinase (JAK) inhibitors improve symptoms and spleen size but often exacerbate anemia, leaving a significant unmet clinical need. Momelotinib, a JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor, has been proposed to address both splenomegaly and anemia through hepcidin suppression. This study critically evaluates the clinical benefit of momelotinib using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H), focusing on the phase 3 trials SIMPLIFY-1 and MOMENTUM. In SIMPLIFY-1, momelotinib demonstrated non-inferiority to ruxolitinib in terms of spleen volume reduction (SVR35 26.5% vs 29.0%) and did not evaluated quality of life as a prespecified outcome, resulting in an ESMO-MCBS:H score indicating no evaluable benefit (NEB). In contrast, in MOMENTUM, conducted in symptomatic, anemic patients previously treated with JAK inhibitors, momelotinib was superior to danazol for MFSAF total symptom score response (≥50% reduction from baseline 25% vs 9%). As no improvement in global health status was observed, MOMENTUM was scored as Grade 1. Interpretation of hematologic benefits remains limited by trial design, as the anemia related outcomes were not primary endpoints and studies were not powered to robustly assess them. Furthermore, the negative SIMPLIFY-2 trial underscores uncertainty in pretreated populations. In conclusion, momelotinib demonstrates a differentiated clinical profile with consistent spleen control and potential hematologic benefits, particularly in anemic patients. However, superiority over other improved JAK inhibitors has not been demonstrated in the pivotal phase 3 trials evaluated. Future trials incorporating anemia-focused primary endpoints and biomarker stratification are warranted to better define its role in myelofibrosis management.
2026-09-26 | The Roles of Genetic and Epigenetic Abnormalities in Essential Thrombocythemia.
Essential thrombocythemia (ET) is a Ph(-) myeloproliferative neoplasm characterized by elevated platelet counts. Patients most often have one of the three following driver mutations: JAK2, MPL, or CALR. However, these mutations are not detected in approximately 10-15% of patients, who are thus referred to as "triple-negative" (TN). Background/Objectives: In recent years, there have been breakthroughs in the genetic diagnosis of hematological diseases and progress in understanding their epigenetic basis. Aim: This study aimed to review the available literature and systematize the current knowledge on the molecular abnormalities in essential thrombocythemia. Particular attention was paid to the impacts of genetic mutations and epigenetic changes-such as abnormalities in non-coding RNA expression, DNA methylation, and histone modifications-on disease development and their clinical significance in patients with essential thrombocythemia. The most important publications on genetic and epigenetic mechanisms in essential thrombocythemia were reviewed and summarized. Methods: A review of the available literature was conducted using selected online databases. Publications from 2003 to 2026 were considered, covering the diagnosis and classification criteria for essential thrombocythemia, its genetic and epigenetic basis, and the associated impacts on the disease course. Conclusions: Although understanding the precise roles of genetic and epigenetic abnormalities in essential thrombocythemia remains challenging, they offer many opportunities for use as new diagnostic biomarkers and for the development of novel targeted treatment options. Further research is needed to better understand the genetic and epigenetic changes occurring in ET.
2026-09-25 | ATM mutations in myelodysplastic neoplasms, acute myeloid leukemia, and myeloproliferative neoplasms: a systematic review.
Ataxia Telangiectasia Mutated (ATM), a central kinase in the DNA damage response, is recurrently altered across these disorders, including myelodysplastic neoplasms (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN), yet its clinical significance remains underrecognized. We conducted a PROSPERO-registered systematic review (CRD420251142673) to evaluate the prognostic and biological impact of ATM alterations in MDS, AML, and MPN. Ten studies met inclusion criteria. In MDS, ATM alterations showed consistent downregulation, hypermethylation, and a predominance of oncogenic missense mutations, with methylation significantly enriched in cases progressing to AML. In AML, reduced ATM gene expression, often driven by miR-100 or miR-181a, was associated with increased blast proliferation, while the ATM genetic variant rs3092856 correlated with chemoresistance and inferior survival. Evidence in MPN/CML, although limited, suggests that ATM polymorphisms, such as rs228593, rs3092856 (C4138T), -5144A>T (rs228589), c.5753G>C, c.346A>G, c.4060C>A, and the germline variant L2307F, contribute to disease susceptibility and adverse prognostic stratification. Collectively, current evidence supports ATM alterations as clinically relevant biomarkers in myeloid malignancies, although their functional role in disease pathogenesis remains incompletely understood.. Rather than establishing ATM merely as a prognostic marker, future efforts should prioritize the characterization of ATM-related therapeutic vulnerabilities and integrate ATM status into treatment-oriented molecular panels to guide precision-based interventions in myeloid diseases.
2026-09-24 | Dual-Driver Myeloproliferative Neoplasm: Concurrent p190 BCR::ABL1 CML and JAK2 V617F Mutation: A Case Report and Literature Review.
The concurrent occurrence of BCR::ABL1 rearrangement and JAK2 V617F mutation is an exceptionally rare phenomenon, with reported frequencies of 0.2%-2.5% in tested myeloproliferative neoplasm (MPN) cohorts and an estimated overall rate of approximately 0.4% in patients screened for both alterations. These molecular drivers are generally considered mutually exclusive, as BCR::ABL1 defines Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), while JAK2 V617F characterizes Ph-negative MPNs. We report a male patient in his 50s with a previously detected JAK2 V617F mutation, initially managed as essential thrombocythemia, who later presented with leukocytosis, macrocytic anemia, thrombocytopenia, and absolute monocytosis. Bone marrow demonstrated marked myeloid hyperplasia with atypical megakaryocytes, comprising scattered dwarf forms together with larger forms with "cloud-like" nuclei and focal reticulin fibrosis (MF-1). These findings, together with the known JAK2 V617F mutation, prompted targeted molecular investigation. High-sensitivity RT-PCR confirmed an isolated e1a2 (p190) BCR::ABL1 transcript, the minor breakpoint cluster region isoform occurring in only 1%-2% of CML cases, with the complete absence of the p210 isoform, alongside a concurrent JAK2 V617F mutation (allele burden 16%). Standard p210-focused quantitative assays would have produced a false-negative result in this case. The patient received first-line asciminib and was subsequently transitioned to dasatinib, with the BCR::ABL1/ABL1 ratio declining from 88.5% at diagnosis to 0.79% at most recent assessment. This case highlights the critical importance of integrated morphologic, cytogenetic, and molecular evaluation in atypical MPN presentations. The admixed megakaryocytic atypia superimposed on myeloid hyperplasia reflected the coexistence of two drivers. Comprehensive profiling, including high-sensitivity RT-PCR capable of detecting the p190 isoform and concurrent JAK2 testing, is essential for accurate diagnosis, prognostication, and therapy selection in these rare dual-driver cases.
cell therapies
2026-07-27 | Impact of High-Risk Mutations and Treatment Intensity in Accelerated-Phase Blast-Phase MPN Without Adverse-Risk Karyotype and TP53.
The prognostic significance of myelodysplasia-related gene mutations (MDS-RGMs), defined by the ELN 2022 classification and Mutation-Enhanced International Prognostic Score System high-risk mutations (MIPSS70-HRM), in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs) remains unclear. We conducted a retrospective study of 101 AP/BP MPN patients with intermediate-risk cytogenetics, excluding TP53 mutations and adverse-risk karyotypes. We evaluated whether MDS-RGM or MIPSS70-HRM predicted treatment response, overall survival (OS), or disease-free survival (DFS) and whether treatment intensity affected OS. Patients included AP (29.7%) and BP (70.3%), with 55% receiving intensive therapy. Allogeneic stem cell transplant (ASCT) significantly improved OS (HR 0.31, 95% CI 0.19-0.50; p < 0.0001), as did AP versus BP at transformation (HR: 0.43, 95% CI 0.26-0.73; p = 0.0016). Among patients ≤ 70 years with ECOG 0-1 (N = 77), ASCT and reversion to chronic-phase MPN (cMPN) were associated with longer OS (p < 0.0001 and p = 0.0475). Treatment intensity alone did not significantly affect OS (p = 0.1991).
2026-06-29 | Thrombocytapheresis as a Bridge Intervention in JAK2-Mutant Myeloproliferative Neoplasm Complicated by Acquired von Willebrand Disease: A Case Report.
Acquired von Willebrand disease (AvWD) in myeloproliferative neoplasms with extreme thrombocytosis causes paradoxical bleeding due to the mechanism of adsorption and ADAMTS13-mediated proteolysis of high-molecular-weight von Willebrand factor (vWF) multimers. When first-line cytoreductive therapy fails due to intolerance or nonadherence, rapid alternatives are limited. We describe a 74-year-old woman with JAK2V617F-mutated myeloproliferative neoplasm and hydroxyurea intolerance who presented with active mucosal bleeding and a platelet count of 952 000/μL. vWF antigen (vWF:Ag) was 0.37 IU/mL (reference range: 0.50-2.00 IU/mL), and vWF Ristocetin Cofactor activity (vWF:RCo) was 0.21 IU/mL (activity/antigen ratio 0.57; reference range 0.7-1.3), consistent with AvWD. A single thrombocytapheresis session on the Fresenius COM.TEC platform reduced the platelet count to 277 000/μL, with prompt cessation of bleeding. Repeat testing at 24 h showed improvement in vWF:RCo to 0.48 IU/mL (ratio 0.68), which likely reflects restoration of functional high-molecular-weight multimers. In this single case, thrombocytapheresis provided rapid and effective platelet reduction for AvWD secondary to myeloproliferative neoplasms when pharmacological cytoreduction is inadequate.
2026-05-22 | The Two-Step Allogeneic Stem Cell Transplant Is Associated with Excellent Engraftment, Improved Survival and Low Nonrelapse Mortality in Patients with Myelofibrosis.
Myelofibrosis is a chronic myeloproliferative disorder primarily affecting older adults, and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. However, HSCT for myelofibrosis presents significant challenges, including high nonrelapse mortality (NRM) and an increased risk of graft failure. In this 20-year retrospective study, we evaluated outcomes for 32 myelofibrosis patients who underwent HSCT at our institution, with particular focus on a two-step transplant approach designed to optimize T-cell dosing by separating the lymphoid and myeloid graft components, with cyclophosphamide administered after the lymphoid infusion and before infusion of CD34-selected stem cells. Eighteen patients underwent transplantation using the two-step approach and demonstrated favorable outcomes, with 1-year and 5-year overall survival (OS) rates of 83% and 68%, respectively. NRM was reduced, with rates of 17% at 1 year and 23% at 5 years. Engraftment was robust, with median neutrophil and platelet recovery at 12 and 19 days, respectively, and a low graft failure rate of 5.9% despite the predominant use of reduced-intensity conditioning and haploidentical donors, compared with 17.5% graft failure among patients receiving a traditional one-step transplant. Across the entire cohort, OS was 66% at 1 year and 54% at 5 years, respectively, with NRM rates of 34% and 42% at 5 years, respectively. The cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was 17% each. These findings suggest that the two-step transplant platform is a viable and effective strategy for improving HSCT outcomes in myelofibrosis, providing lower NRM and favorable engraftment profiles. Further studies are warranted to validate these results and refine HSCT protocols to reduce transplant-related mortality and improve long-term survival in patients with myelofibrosis.
2026-05-13 | Prospects of Chimeric Antigen Receptor T-Cell Therapy in Myelofibrosis: From Immunopathogenesis to Therapeutic Strategies.
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4-CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification.
2026-04-26 | Acute myeloid leukemia after myeloproliferative neoplasms: Real-world outcomes in the new treatment era in the United States.
Progression to acute myeloid leukemia (AML) is a rare complication of myeloproliferative neoplasms (MPNs) with limited treatment options and median overall survival (OS) of 3-6 months. The treatment of AML has been revolutionized in recent years with the introduction of novel targeted therapies including the BCL2 inhibitor venetoclax (VEN). However, evidence regarding outcomes in patients with post-MPN AML remains limited. To evaluate the impact of novel therapies on the outcomes of patients with post-MPN AML, the authors conducted a retrospective analysis of 392 patients who were diagnosed with post-MPN AML during 2014-2024 in the United States and were included in the Flatiron Health Research Database. Although the proportion of patients treated with lower-intensity therapies (LIT) including VEN in combination with hypomethylating agents increased over time, OS was very similar among patients diagnosed before and after VEN approval (median OS, 7.1 [95% confidence interval (CI), 5.7-9.5] months vs. 7.6 [95% CI, 5.8-10.1] months; p = .39). Only 15% of post-MPN AML patients underwent an allogeneic hematopoietic cell transplant (allo-HCT). Those who received allo-HCT experienced better OS than patients who did not receive allo-HCT (median OS, 20.5 [95% CI, 15.4-36.2] months vs. 5.8 [95% CI, 5.0-6.8] months; p < .01). Although patients treated with intensive chemotherapy (IC) had longer OS than those treated with LIT (hazard ratio, 1.95; 95% CI, 1.12-3.41; p = .02), patients receiving IC and LIT as a bridge to allo-HCT had comparable OS (p = .37). This study highlights allo-HCT as the only potentially curative option with both IC and LIT serving as effective bridging therapies.
proteins
2026-09-18 | Molecular Response, Event-Free Survival, and Treatment-Free Remission in Myeloproliferative Neoplasms: Update and Review with Insights from MPN Asia 2026.
Therapeutic goals in BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are evolving to include biologically anchored measures of disease modification with control of blood counts, splenomegaly, and symptoms. Disease modification endpoints and their linkage to survival in MPNs were central to the framework of MPN Asia 2026, which took place in Seoul. This review summarizes key themes from MPN Asia 2026 and relevant recent literature, examining the evolving roles of molecular response and long-term clinical benefits within a broader disease-modification framework across polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Clinical trials with ropeginterferon alfa-2b were central to the discussions given these studies have contributed to the evolving paradigm of disease modification in MPNs, underscoring the importance of molecular response and event-free survival (EFS) in MPN management. In PV, ropeginterferon alfa-2b treatment provides a clinical model linking durable hematologic control and deep JAK2V617F variant allele frequency (VAF) reduction with improved long-term outcomes such as EFS, and prospective treatment-discontinuation strategies. Data from Europe and Asia supports the importance of early disease control, adequate interferon exposure, and longitudinal molecular monitoring. In ET, randomized data with ropeginterferon alfa-2b and emerging new treatment approaches such as lysine-specific demethylase 1 inhibition and mutant CALR-directed therapy are incorporating molecular endpoints into clinical development. However, the association between VAF reduction and thrombosis prevention, disease modification, EFS, and treatment-free remission (TFR) need to be elucidated. In MF, molecular profiling is already integral to prognostication and treatment selection, and disease modification assessment will likely require endpoints encompassing more than symptoms and spleen response, such as anemia response, bone marrow fibrosis change, clonal evolution, patient-reported outcomes, and importantly progression-free and overall survival. Molecular response, clonal suppression, prevention of vascular and progression events, survival outcomes such as EFS and TFR play increasingly important roles in MPN management.
2026-09-16 | Type 1 interferon perturbates clonal competition by reshaping human blood development.
Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.
2026-09-01 | Efficacy and Safety of Ropeginterferon Alfa-2b in Pregnant Women With Myeloproliferative Neoplasms: Case Series of Three Subtypes and Review.
Managing myeloproliferative neoplasms (MPNs) during pregnancy is challenging due to increased thrombotic risk and limited cytoreductive options. Ropeginterferon alfa-2b (ropeginterferon), a long-acting mono-pegylated interferon, has limited data in this setting. We report a Korean multicenter case series of four pregnancies across MPN subtypes, including prefibrotic/early primary myelofibrosis, essential thrombocythemia, and polycythemia vera. Ropeginterferon was used during pregnancy or prior to conception (250-500 μg every 2-12 weeks) with aspirin and/or low-molecular-weight heparin. Hematologic responses were sustained throughout pregnancy without treatment-limiting adverse events. All pregnancies resulted in live births without major maternal or neonatal complications. Within the limits of a small retrospective series, ropeginterferon appeared to be a feasible cytoreductive option in these MPN pregnancies, including pre-conception and intra-pregnancy use; these preliminary observations warrant confirmation in larger prospective studies.
2026-08-26 | Neutrophil-to-lymphocyte ratio as a gene-specific biomarker of JAK2-driven inflammation across CHIP and myeloproliferative neoplasms.
The neutrophil-to-lymphocyte ratio (NLR) has emerged as a mechanistically informative biomarker in clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPNs), although its clinical utility is strongly mutation dependent. NLR is markedly elevated in JAK2V617F-mutated CHIP and MPNs, reflecting neutrophil-driven myeloproliferation, whereas it remains largely unchanged in TET2, DNMT3A, and ASXL1 mutations despite substantial IL-1β- and IL-6-mediated inflammation. This apparent paradox highlights distinct inflammatory programs generated by different driver mutations, with JAK2 promoting neutrophilia and epigenetic mutations primarily activating macrophage-mediated innate immunity. In polycythemia vera, elevated NLR independently predicts thrombosis, myelofibrotic progression, and mortality. Similar prognostic value has been reported in essential thrombocythemia and myelofibrosis, particularly among patients with JAK2 mutations. Beyond risk stratification, NLR also functions as a pharmacodynamic biomarker. During treatment with ropeginterferon alfa-2b, reductions in NLR parallel decreases in JAK2V617F allele burden, whereas persistent NLR elevation during hydroxyurea therapy identifies patients at higher risk of thrombosis and adverse outcomes. Conversely, the CANTOS trial demonstrates that patients with TET2-mutated CHIP derived marked cardiovascular benefit from IL-1β inhibition despite NLR providing limited biological information, underscoring the need for complementary biomarkers in non-JAK2 CHIP. This review integrates mechanistic, clinical, and therapeutic evidence supporting mutation-specific inflammatory biomarkers and proposes NLR-guided strategies for risk assessment, treatment monitoring, and precision management in MPNs and CHIP.
2026-06-26 | A Hidden Driver Mutation in Myeloproliferative Neoplasms: SH2B3 and Diagnostic Implications and Response to Ropeginterferon Alfa-2b.
Myeloproliferative neoplasms (MPNs) are commonly linked to driver mutations in the JAK2, MPL, and CALR genes. In contrast, SH2B3 (LNK) mutations are uncommon and remain an under-characterized contributor to dysregulated JAK-STAT signaling. The clinical features and treatment responsiveness of SH2B3-mutated MPNs are not well defined, and data on outcomes with ropeginterferon alfa-2b in this molecular subgroup are limited. We report a 75-year-old man who presented for evaluation of headache, generalized bone pain, and night sweats and was found to have abnormal blood counts including persistent leukocytosis, erythrocytosis, and thrombocytosis. Prior molecular testing was negative for JAK2, MPL, and CALR mutations. Bone marrow examination showed hypercellularity with panmyelosis, mild megakaryocytic atypia, and WHO grade 1 reticulin fibrosis. Hematologic next-generation sequencing identified a pathogenic SH2B3 c.1481C>G (p.Ser494*) nonsense mutation, predicted to result in a loss of SH2B3's C-terminal regulatory domain. Given the tri-lineage cytoses and marrow findings, a diagnosis of SH2B3-mutated MPN was established. He was started on ropeginterferon alfa-2b, resulting in resolution of his symptoms and complete hematologic response (WBC ≤ 10 × 103/μL, Hct ≤ 45%, and PLT ≤ 400 × 103/μL) within 12 weeks, without the need for phlebotomy or treatment-limiting adverse effects. This case underscores the clinical significance of SH2B3 mutations as a driver of triple-negative MPNs and supports their inclusion in molecular evaluation when classical mutations are absent. The favorable clinical and hematologic response to ropeginterferon alfa-2b suggests that interferon-based therapy may be effective in SH2B3-mutated MPNs.
antibodies
2026-08-19 | Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.
Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR-MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.
2026-06-28 | Beyond the JAK2 mutation: The inflammasome, clonal stability, and the thrombotic niche in myeloproliferative neoplasms.
Philadelphia-negative myeloproliferative neoplasms (MPNs) carry a disproportionate thrombotic burden that cannot be explained by conventional cardiovascular risk factors or blood count parameters alone. This review synthesizes emerging evidence positioning MPN-associated thrombosis as a distinct pathobiologic entity, clonal thrombo-inflammation, driven by the convergence of somatic mutations and innate immune activation. We examine the continuum from clonal hematopoiesis of indeterminate potential (CHIP) to overt MPN, highlighting how Janus kinase 2 (JAK2)V617F and other driver mutations reprogram myeloid cells toward hyperinflammatory phenotypes. A recurring mechanistic theme is NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and interleukin-1 family signaling, which may create a feed-forward loop in which mutant clones amplify inflammatory circuits that, in turn, may enhance clonal fitness and contribute to thrombogenicity across multiple cellular compartments. We propose the 'thrombotic niche' as a conceptual, multi-compartment model encompassing mutant hematopoietic stem cells, hyperinflammatory myeloid effectors, hyperreactive platelets, platelet-leukocyte aggregates, and activated endothelium, but it remains a hypothesis-generating framework that lacks direct prospective clinical validation. Current cytoreductive strategies inadequately address this underlying biology, leaving substantial residual vascular risk. Emerging anti-inflammatory and anti-clonal strategies targeting interleukin-1 beta (IL-1β) (canakinumab), mutant-selective JAK2 inhibition, NLRP3 inflammasome blockade, and P-selectin-mediated adhesion are biologically plausible, but their ability to reduce thrombotic events in MPN remains unproven and should be viewed as hypothesis-generating rather than established clinical benefit. We conclude by outlining a translational research agenda integrating inflammation-aware risk stratification, niche-directed imaging, and spatial multi-omics to guide precision anti-inflammatory interventions in MPN.
2026-06-27 | Neutrophil extracellular traps in thrombosis of hematologic malignancies: Underlying mechanisms and therapeutic opportunities (Review).
Patients with cancer, particularly those diagnosed with hematological malignancies, exhibit thrombus incidence rates that exceed those observed in the general population by a substantial margin, and this elevated risk is associated with worse clinical outcomes. Neutrophil extracellular traps (NETs), which are web‑like structures released by neutrophils as part of their innate immune repertoire, drive coagulation and vascular occlusion by supplying a physical scaffold, recruiting procoagulant factors, and cleaving tissue factor pathway inhibitors. In hematological malignancies, emerging evidence points to NET overproduction and dysregulation as key drivers of thrombosis, representing a previously underappreciated mechanistic axis. The present review focuses on the molecular mechanisms by which NETs promote thrombosis, specifically on thrombosis associated with hematological malignancies (such as myeloproliferative neoplasm, acute myeloid leukemia, Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia), and also explores the clinical translation potential of NET‑related therapies. The present study offers a potential basis for refining current approaches to coagulation risk reduction in patients with hematological malignancies.
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-04-20 | From JAK to CALR: redefining therapeutic targets in myeloproliferative neoplasms.
This review highlights the emergence of CALR as a promising therapeutic target in CALR-mutated myeloproliferative neoplasms. While current JAK inhibitors alleviate symptoms and reduce thrombosis risk, they lack clonal specificity, have a limited impact on the natural history of disease, and are limited by toxicity and resistance. In contrast, CALR mutations generate a unique, disease-specific neoepitope that drives disease pathogenesis through aberrant MPL activation and is accessible on the cell surface, making it an ideal immunologic and antibody target. Preclinical and early clinical advances - including monoclonal antibodies, bispecific T-cell engagers, CAR-T therapies, antibody-drug conjugates, and peptide/viral vector vaccines - have demonstrated selective activity against CALR-mutant clones while sparing normal hematopoiesis, with encouraging evidence of molecular remissions and disease modification. Although challenges such as immune tolerance remain, mutant CALR-directed therapies represent a potential transformative shift in essential thrombocythemia, and primary myelofibrosis treatment.
other
2026-02-10 | The Role and Impact of Non-driver Gene Mutations in Myelofibrosis.
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis and potential progression to a blast phase. This review provides a comprehensive overview of the current molecular landscape of MF beyond canonical driver mutations (JAK2, MPL or CALR), emphasizing insights gained from murine models that served as valuable tools for understanding disease mechanisms. High-throughput next-generation sequencing (NGS) has markedly enhanced our understanding of the molecular basis of MF, identifying numerous mutations beyond the canonical driver genes JAK2, MPL, and CALR, which are present in about 80% of patients. Additional mutations affect genes involved in DNA methylation (TET2, DNMT3A, IDH1, IDH2), histone modification (ASXL1, EZH2), mRNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), signaling pathways (CBL, NRAS, KRAS), and key transcription factors (RUNX1, NFE2, TP53). The presence and combination of these alterations influence clinical presentation, prognosis, and therapeutic response. This review offers an updated synthesis of the evolving molecular landscape of MF, highlighting how the intricate interplay among genetic alterations has deepened our understanding of disease heterogeneity, allowing refined risk stratification and therapeutic planning. Advances emerging from molecular research and experimental models are progressively translating into clinical practice, promoting more personalized and targeted approaches to the management of MF.
2026-01-08 | Targeting the JAK2V617F mutant hematopoietic microenvironment in myeloproliferative neoplasm
The acquired JAK2V617F mutation is predominantly detected in hematopoietic stem cells(HSCs), leading to myeloproliferative neoplasms(MPN). Emerging evidence shows that JAK2V617F bearing cells remodel their microenvironment by dysregulating cytokines, and altering adhesion molecules, with histopathological changes in the spleen and liver that influence thrombosis and disease progression. However, how JAK2V617F bearing cells interact with and modify niche factors to promote MPN progression remains insufficiently defined and represents an important therapeutic opportunity. This review focuses on the effect of mutant HSCs on the BM niche, emphasizing key signaling pathways such as IL-β1, TPO/MPL, TGF-β1, VEGF, CXCR4/CXCL12, and altered metabolism. Understanding these dysregulated interactions provides a rationale for therapies that directly target the niche components. Current therapies, including JAK inhibitors, partially address symptoms but are limited by resistance and off-target effects, whereas emerging niche-directed strategies such as such as CXCR4 antagonists, TGF-β1 blockers and metabolic modulators, may restore normal hematopoiesis and overcome ruxolitinib resistance. Therefore, understanding and modulating these HSC-niche interactions advances a path toward durable and transformative therapies for MPNs.
2025-12-19 | Genome editing for treatment of JAK2 V617F-driven myeloproliferative neoplasms
Abstract JAK2 V617F is a common haematological driver mutation and underlies most cases of myeloproliferative neoplasms (MPNs). Reducing variant allele frequency (VAF) is an important treatment goal, but no current treatment modalities fully and specifically inhibit mutant signalling. Thus, the consequences of V617F inactivation are unclear, including whether selective inhibition of V617F signalling will eradicate mutant cells due to oncogene addiction. Here, we describe an allele-selective CRISPR-Cas genome editing strategy that achieves selective and efficient JAK2 V617F inactivation in patient stem and progenitor cells. We show that JAK2 V617F heterozygous cells are not oncogene addicted and maintain viability and differentiation potential upon loss of their mutant allele. In contrast, homozygous mutant cells are eradicated upon deletion of both mutant alleles. Across in vitro , organoid, xenotransplantation and single-cell assays, selective deletion of V617F alleles reverts MPN hallmarks including erythroid clonogenicity, inflammatory gene expression signatures, as well as myelofibrosis and splenomegaly phenotypes in an in vivo xenograft model. Collectively, our results show that is it possible to revert heterozygous JAK2 V617F mutant cells to a normal phenotype and suggest that ex vivo genome editing of stem and progenitor cells may be a viable treatment option to achieve rapid and deep reductions in VAF.
2025-10-08 | ALPHA-TOCOPHEROL AND G-CSF CHANGE EXPRESSION OF GENES ASSOCIATED WITH DIFFERENTIATION OF K562 CHRONIC MYELOID LEUKEMIA CELLS DOWNREGULATING EMT-ASSOCIATED STEMNESS BIOMARKERS.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a block of myeloid differentiation, finally resulting in the uncontrolled expansion of CML stem cells in a phase of blast crisis of the disease. Tyrosine kinase inhibitors (TKI) are effective in delaying CML progression for a long time. Nevertheless, CML cells become resistant to TKI over time. Therefore, the search for alternative and complementary therapies, including differentiation therapy, is currently in the limelight. The aim of the study was to explore the differentiation potential of alpha-tocopherol and granulocyte-colony stimulating factor (G-CSF) by analyzing the gene expression of several factors critical for myeloid differentiation of K562 CML cells, as well as some key leukemic stemness transcription factors. The mRNA expression of C/EBPα (CCAAT/enhancer binding protein alpha), neutrophil-granulocytic factor TNAP (tissue non-specific alkaline phosphatase), E-cadherin, SNAIL, OCT4, and PLAP (placental-like alkaline phosphatase) was studied by qRT-PCR in K562 cells exposed to alpha-tocopherol or G-CSF. K562 cell exposure to alpha-tocopherol or G-CSF resulted in the CEBPB, CDH1, and ALPL gene upregulation. At the same time, down-regulation of EMT-associated markers SNAIL, PLAP, and OCT4 (SNAI1, ALPP, and POU5F1 genes) was demonstrated. The inverse relationship between expression of the genes of leukemic stemness cell markers SNAIL, OCT4, and PLAP and the genes of myeloid differentiation markers C/EBPα, TNAP, and E-cadherin in K562 cells exposed to alpha-tocopherol or G-CSF suggests the activation of the molecular pattern of myeloid differentiation in this setting.
2025-09-18 | Statins enhance the efficacy of pegylated interferon-alfa2 in Philadelphia-negative chronic myeloproliferative neoplasms.
Chronic inflammation may be a key driving force in the development and progression of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Statins, commonly used to lower cholesterol, also possess antiproliferative, proapoptotic, and anti-inflammatory properties that may be beneficial in the treatment of patients with MPN. This retrospective cohort study investigated whether statin use, in addition to standard cytoreductive therapy, shortens the time required to achieve hematological and molecular responses, while allowing for lower cytoreductive drug dosages. A total of 129 patients were included, with 53 receiving statins from diagnosis. The study found that statin users achieved complete hematological response (CHR) significantly faster than nonusers (median time: 8 vs 18 months; hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.4-3.1; P = .0003). Among patients treated with pegylated interferon-alfa2 (IFN-α2), the CHR rate was 97% in statin users vs 83% in nonusers (HR, 2.5; 95% CI, 1.5-3.9; P = .0004), and a higher proportion of statin users sustained CHR throughout follow-up. Additionally, IFN-treated statin users received a significantly lower mean dose of IFN-α2. A dose-response relationship was observed, with higher statin intensity associated with an increase of CHR. Furthermore, statin use was significantly associated with achieving a partial molecular response among IFN-α2-treated patients (HR, 2.6; 95% CI, 1.1-6.0; P = .029). No significant association was observed in hydroxyurea (HU)-treated patients. These findings suggest that statins may enhance the efficacy of IFN-α2 in patients with MPN, while their benefit in HU-treated patients remains unclear. Prospective studies are warranted to further explore the therapeutic potential of statins in MPNs.
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Drug Discovery Landscape
3 orphan drug designations for Myeloproliferative neoplasm.
3 orphan drug designations for Myeloproliferative neoplasm.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adenosine triphosphate type 1 competitive inhibitor of JAK2 V617F tyrosine kinase | small molecules | FDA | Eli Lilly and Company | |
pomalidomide | small molecules | FDA | Celgene Corporation | |
lestaurtinib | small molecules | FDA | — | Teva Branded Pharmaceutical Products R&D, 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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