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<p>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.</p> Graphical abstract <p>The clonal thrombo‑inflammation cycle in myeloproliferative neoplasms. A self‑perpetuating feed‑forward loop links the JAK2V617F‑mutant clone, NLRP3 inflammasome activation, and a prothrombotic niche (platelets, NETs, activated endothelium). Disrupting this loop, by targeting the clone, the inflammasome, or thrombotic effectors, is the central therapeutic strategy to reduce thrombosis.</p> <p></p>

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Beyond the JAK2 mutation: The inflammasome, clonal stability, and the thrombotic niche in myeloproliferative neoplasms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月28日

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  • Amr Ali Mohamed Abdelgawwad El-Sehrawy,
  • Mutaz Jamal Al-khreisat,
  • Makhfirat Kibriyeva,
  • Islamova Dilbar,
  • Fotima Axmedova,
  • Jbar Abady Mohammed,
  • Swati Mishra,
  • Navin Kumar Tailor

摘要

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.

Graphical abstract

The clonal thrombo‑inflammation cycle in myeloproliferative neoplasms. A self‑perpetuating feed‑forward loop links the JAK2V617F‑mutant clone, NLRP3 inflammasome activation, and a prothrombotic niche (platelets, NETs, activated endothelium). Disrupting this loop, by targeting the clone, the inflammasome, or thrombotic effectors, is the central therapeutic strategy to reduce thrombosis.