2026-07-02 | Fibrocytes drive JAK2V617F-mutated myelofibrosis: pitavastatin reverses marrow fibrosis and anemia.
Bone marrow (BM) fibrosis in primary and post-polycythemia vera/essential thrombocythemia myelofibrosis (MF) has traditionally been considered a reactive process driven by cytokines, such as transforming growth factor (TGF)-β1, primarily produced by neoplastic megakaryocytes and platelets. These cytokines promote the differentiation of wild-type mesenchymal stromal cells into collagen- and fibronectin-producing myofibroblasts, thereby inducing BM fibrosis. However, hematopoietic-derived collagen-producing cells of monocyte lineage, termed fibrocytes, have also been implicated in this process. Here, we demonstrate that fibrocytes constitute a major collagen-producing cell population in the BM of patients with JAK2V617F-mutated MF, with additional contributions from myofibroblasts. Analysis of BM samples from patients with JAK2V617F-mutated myeloproliferative neoplasms (MPNs) revealed that fibrocytes accounted for nearly two-thirds of collagen-producing cells, whereas myofibroblasts represented a smaller subset. Using BM-derived fibrocytes from Jak2V617F transgenic mice (Jak2V617F mice), we performed a high-throughput drug screen and identified statins as inhibitors of fibrocyte proliferation in vitro. In vivo, pitavastatin treatment reduced fibrocyte numbers, ameliorated BM fibrosis, and improved anemia in Jak2V617F mice. Pitavastatin also decreased TGF-β1 production by neoplastic fibrocytes, resulting in reduced myofibroblast expansion. Peripheral blood-derived fibrocytes from patients with JAK2V617F-mutated MPNs were similarly sensitive to pitavastatin in vitro. Together, these findings suggest that fibrocytes substantially contribute to BM fibrosis in JAK2V617F-mutated MF and support further investigation of pitavastatin as a potential antifibrotic strategy in this molecular subset.
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2026-06-24 | Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms.
Myeloproliferative neoplasms (MPN) comprise a heterogenous group of hematological malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Current therapeutic strategies rely on cytoreductive approaches that mitigate disease burden and thromboembolic risk but are not curative. Allogeneic stem cell transplantation remains the only curative option, underscoring the need for novel therapeutic strategies. We previously identified hypoxia-inducible factor 1 (HIF-1) as a selective vulnerability in JAK2V617F-positive cells, but the underlying metabolic mechanisms remain incompletely defined. In vitro studies utilized 32D cells transduced with an empty vector control, Jak2WT, or Jak2V617F. To evaluate metabolic dependencies, CRISPR-Cas9 was used to generate Slc2a1 (GLUT1) and Slc2a3 (GLUT3) knockout clones, which were subsequently characterized via RNA sequencing, extracellular flux analysis, and cellular fitness assays (proliferation, viability, and apoptosis). Pharmacological targeted inhibition of GLUT1/3 was evaluated in human JAK2V617F-mutated post-MPN AML cell lines (SET-2, HEL), primary patient-derived cells and a Jak2V617F knock-in mouse model. Combinatorial efficacy was assessed using the JAK1/2 inhibitor ruxolitinib. JAK2V617F induced HIF-1-dependent metabolic reprogramming, characterized by increased glycolytic flux and oxidative metabolism. Complete abrogation of glucose uptake occurred only upon combined loss of GLUT1 and GLUT3 in Jak2V617F cells, revealing functional redundancy between these transporters that sustains enhanced glycolysis. Disruption of glucose uptake selectively induced stress-associated transcriptional programs and replication stress, triggering an S-phase arrest that culminated in apoptosis and impaired viability, specifically in Jak2V617F cells. In vivo, pharmacological inhibition of HIF-1 or GLUT induced a reorganization of erythropoiesis to the spleen but did not ameliorate core disease features. In contrast, in vitro GLUT inhibition robustly reduced cell viability in human SET-2 and HEL cell lines and impaired proliferation, viability, and colony formation in patient-derived PBMCs. Collectively, these findings establish HIF-1-driven glucose metabolism as a metabolic vulnerability in JAK2V617F-positive MPN. The selective exhaustion of patient-derived clones defines the HIF-1-GLUT1/3 axis as a central, targetable bottleneck. These data provide a mechanistic rationale for further investigation of HIF-1 or GLUT inhibitors, suggesting that targeting this fundamental requirement may help overcome clinical limitations to achieve disease modification and eradicate the malignant clone.
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2026-06-22 | Citrullinated Histone 3 as a Marker of NETosis at Opposite Ends of Hemostasis: Evidence From Thrombosis-Prone MPN and Bleeding-Prone Hemophilia.
BackgroundNeutrophil extracellular trap (NET) formation has emerged as a key driver of thrombosis in myeloproliferative neoplasms (MPNs). Its role in congenital bleeding disorders, however, remains unexplored.ObjectivesTo investigate circulating citrullinated histone H3 (cit-H3), a marker of NETosis, in thrombosis-prone MPNs and bleeding-prone severe hemophilia A.MethodsIn a cross-sectional study, plasma cit-H3 was quantified by ELISA in patients with JAK2-mutated polycythemia vera or essential thrombocythemia, patients with severe hemophilia A, and matched healthy controls. Clinical and laboratory data were analyzed for associations with cit-H3 levels.ResultsEighty-nine participants were included: 26 with myeloproliferative neoplasms (MPNs), 31 with severe hemophilia A, and 32 healthy controls. Demographic characteristics were comparable across groups, though comorbidities were more frequent in MPNs. Laboratory analyses confirmed expected disease-specific differences, including elevated leukocyte, neutrophil, and platelet counts in MPNs and prolonged activated partial thromboplastin time in hemophilia A. Circulating citrullinated histone H3 (cit-H3) levels differed significantly among groups (p < 0.001), being lowest in controls, intermediate in MPNs, and highest in hemophilia A. Within disease groups, cit-H3 levels were unaffected by clinical variables such as MPN subtype, aspirin use, phlebotomy history, or factor replacement regimen.ConclusionsElevated circulating cit-H3 levels, suggestive of increased NETosis activity, were observed in both thrombosis-prone MPNs and bleeding-prone hemophilia A. These exploratory findings suggest a possible association between NET formation and thromboinflammatory processes across distinct hemostatic disorders.
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