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
3,139 drug discovery papers related to Myeloproliferative neoplasm, with 6 first-in-class and 45 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
3,139 drug discovery papers related to Myeloproliferative neoplasm, with 6 first-in-class and 45 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-10 | Glutamate accumulation in myelofibrosis microenvironment rewires mesenchymal stromal cells metabolic and epigenetic profiles.
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by bone marrow (BM) fibrosis, osteosclerosis, and a proinflammatory tumor microenvironment (TME). The interplay between malignant hematopoietic stem cells and mesenchymal stromal cells (MSCs) drives disease progression. Although glutamate has been implicated in various cancers, its contribution to MF pathogenesis remains unclear. High-performance liquid chromatography (HPLC) profiling was performed on sera from MF patients and healthy controls (HCs) to identify alterations in amino acid abundance. The proteomic profiles of MF- and HC-derived MSCs were assessed by mass spectrometry. Functional assays in glutamate- and fumarate-treated MSCs were used to investigate metabolic, epigenetic, and phenotypic changes by HPLC, real-time PCR, flow cytometry, immunofluorescence, and Azan-Mallory staining. The therapeutic potential of metabotropic glutamate receptor 5 (mGluR5) inhibition was evaluated using in vitro and in vivo models. Glutamate emerged as the most enriched amino acid in MF sera. In MSCs, glutamate supplementation induced intracellular fumarate accumulation, mediated by increased expression of α-ketoglutarate dehydrogenase components and downregulation of fumarate hydratase activity. Fumarate treatment recapitulated an upregulation of oxidative phosphorylation, also enhancing mitochondrial ROS. Both fumarate and glutamate induced epigenetic remodeling, as shown by accumulation of 5-methylcytosine (5mC) and H3K36me2, which was also confirmed in primary MF-MSCs. Glutamate and fumarate induced a senescent phenotype in MSCs, characterized by increased β-galactosidase activity, oxidative stress and SASP-related genes induction. Both metabolites also promoted collagen deposition, supporting their involvement in fibrotic remodeling. Notably, selective inhibition of metabotropic glutamate receptor 5 (mGluR5) by UBP310 or UBP296 attenuated glutamate-driven senescence, reduced fumarate-associated epigenetic changes and limited collagen deposition in vitro and in vivo, supporting a central role for glutamate signaling in stromal dysfunction and fibrotic niche remodeling. This study identifies glutamate as a key metabolic and signaling factor in MF microenvironment. Glutamate rewires MSC metabolism via fumarate accumulation, drives epigenetic reprogramming, and induces senescence and fibrotic transformation. Targeting mGluR5 may therefore represent a promising therapeutic strategy to mitigate MSC dysfunction and bone marrow fibrosis in MF.
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.
2026-06-28 | 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.
2026-07-10 | Glutamate accumulation in myelofibrosis microenvironment rewires mesenchymal stromal cells metabolic and epigenetic profiles.
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by bone marrow (BM) fibrosis, osteosclerosis, and a proinflammatory tumor microenvironment (TME). The interplay between malignant hematopoietic stem cells and mesenchymal stromal cells (MSCs) drives disease progression. Although glutamate has been implicated in various cancers, its contribution to MF pathogenesis remains unclear. High-performance liquid chromatography (HPLC) profiling was performed on sera from MF patients and healthy controls (HCs) to identify alterations in amino acid abundance. The proteomic profiles of MF- and HC-derived MSCs were assessed by mass spectrometry. Functional assays in glutamate- and fumarate-treated MSCs were used to investigate metabolic, epigenetic, and phenotypic changes by HPLC, real-time PCR, flow cytometry, immunofluorescence, and Azan-Mallory staining. The therapeutic potential of metabotropic glutamate receptor 5 (mGluR5) inhibition was evaluated using in vitro and in vivo models. Glutamate emerged as the most enriched amino acid in MF sera. In MSCs, glutamate supplementation induced intracellular fumarate accumulation, mediated by increased expression of α-ketoglutarate dehydrogenase components and downregulation of fumarate hydratase activity. Fumarate treatment recapitulated an upregulation of oxidative phosphorylation, also enhancing mitochondrial ROS. Both fumarate and glutamate induced epigenetic remodeling, as shown by accumulation of 5-methylcytosine (5mC) and H3K36me2, which was also confirmed in primary MF-MSCs. Glutamate and fumarate induced a senescent phenotype in MSCs, characterized by increased β-galactosidase activity, oxidative stress and SASP-related genes induction. Both metabolites also promoted collagen deposition, supporting their involvement in fibrotic remodeling. Notably, selective inhibition of metabotropic glutamate receptor 5 (mGluR5) by UBP310 or UBP296 attenuated glutamate-driven senescence, reduced fumarate-associated epigenetic changes and limited collagen deposition in vitro and in vivo, supporting a central role for glutamate signaling in stromal dysfunction and fibrotic niche remodeling. This study identifies glutamate as a key metabolic and signaling factor in MF microenvironment. Glutamate rewires MSC metabolism via fumarate accumulation, drives epigenetic reprogramming, and induces senescence and fibrotic transformation. Targeting mGluR5 may therefore represent a promising therapeutic strategy to mitigate MSC dysfunction and bone marrow fibrosis in MF.
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.
2026-06-28 | 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.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Myeloproliferative neoplasm.
3 orphan drug designations for Myeloproliferative neoplasm.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adenosine triphosphate type 1 competitive inhibitor of JAK2 V617F tyrosine kinase | small molecules | FDA | 2011-03-03 | — | Eli Lilly and Company |
pomalidomide | small molecules | FDA | 2010-09-21 | — | Celgene Corporation |
lestaurtinib | small molecules | FDA | 2009-09-03 | — | Teva Branded Pharmaceutical Products R&D, Inc. |
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