Megakaryocyte dysfunction

Current understanding

Atypical megakaryocyte morphology and clustering is a histologic hallmark of MPN, and abnormal megakaryocytes drive marrow fibrosis via TGF-beta and PDGF release.

Evidence log

• 2026-09-01 — Fibrocytes drive JAK2V617F-mutated myelofibrosis: pitavastatin reverses marrow fibrosis and anemia.: Preclinical JAK2V617F MF data challenge the megakaryocyte-centric fibrosis model by showing monocyte-derived fibrocytes account for the majority of marrow collagen production, suggesting megakaryocyte-driven TGF-β/PDGF signaling operates alongside — rather than as the sole source of — collagen-producing effectors. (novelty: 4)
• 2026-07-17 — Philadelphia-negative myeloproliferative neoplasms and acquired von Willebrand syndrome: only pertinent at diagnosis?: AVWS at MPN diagnosis correlated with proliferative burden (polycythemia and platelets >700×10⁹/L) rather than thrombocytosis alone, arguing that megakaryocyte-driven platelet mass is one contributor among several to VWF adsorption/proteolysis at diagnosis. (novelty: 3)
• 2026-08-25 — Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.: In myelofibrosis models, C3-reprogrammed splenic reticular cells create pro-fibrotic extramedullary niches that support clonal megakaryocyte-driven fibrogenesis, extending the megakaryocyte-stromal fibrosis axis to the splenic microenvironment. (novelty: 5)
• 2026-06-12 — CRETA (Clopidogrel Responsiveness in Essential ThrombocithemiA): CRETA framing invokes accelerated platelet turnover from clonal megakaryopoiesis as a mechanism by which newly generated, uninhibited platelets dilute clopidogrel’s antiplatelet effect in ET, linking megakaryocyte hyperactivity to antiplatelet pharmacodynamics. (novelty: 3)
• 2026-05-26 — JAK2V617F Mutated Endothelium Has a Stem Cell Potential in Primary Myelofibrosis: a New Disease Ontogenesis for Chronic Myeloproliferative Disorders: If JAK2V617F-mutated hemogenic endothelium acts as the malignant stem cell pool in PMF, the atypical megakaryocyte clone driving fibrosis would derive from an endothelial-origin clonal hierarchy rather than a canonical HSC clone. (novelty: 5)
• 2026-04-23 — Bomedemstat vs Hydroxyurea for Essential Thrombocythemia (MK-3543-007): Bomedemstat’s clinical activity in ET (phase 3 vs hydroxyurea) is mechanistically tied to LSD1-dependent megakaryopoiesis, implicating LSD1 as a regulator of pathologic megakaryocyte expansion that drives ET thrombocytosis. (novelty: 4)

Open questions

Related mechanisms

• bone-marrow-fibrosis
• jak-stat-signaling