Increased risk of thrombosis in JAK2 V617F-positive patients with primary myelofibrosis and interaction of the mutation with the IPSS score

Barbui, Tiziano; Ghirardi, Arianna; Carobbio, Alessandra; Masciulli, Arianna; Carioli, Greta; Finazzi, Maria Chiara; Bellini, Marta; Rumi, Elisa; Vanni, Daniele; Borsani, Oscar; Passamonti, Francesco; Mora, Barbara; Brociner, Marco; Guglielmelli, Paola; Paoli, Chiara; Alvarez‐Larrán, Alberto; Triguero, Ana; Garrote, Marta; Pettersson, Helna; Andréasson, Björn; Barosi, Giovanni; Vannucchi, Alessandro M.

doi:10.1038/s41408-022-00743-0

Cited by 7 publications

(6 citation statements)

References 9 publications

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“…17,18 Future studies will determine whether the increased PIEZO1 expression observed in platelets from PMF patients might contribute to increased thrombotic risk that is described in these patients. 63,64 In conclusion, our study highlights the involvement of the mechanosensor PIEZO1 in regulating Mk maturation and proplatelet biogenesis. The upregulation of PIEZO1 in PMF suggests its potential contribution to the aberrant megakaryopoiesis observed in this disease.…”

Section: Discussionmentioning

confidence: 56%

“…In addition, the central role of PIEZO1 as a driver of a mechanothrombotic pathway has been demonstrated in different scenarios such as diabetes and hypertension 17,18 . Future studies will determine whether the increased PIEZO1 expression observed in platelets from PMF patients might contribute to increased thrombotic risk that is described in these patients 63,64 …”

Section: Discussionmentioning

confidence: 98%

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Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis

Abbonante,

Karkempetzaki,

Leon

et al. 2024

American J Hematol

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Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and disease are still partially understood. We found PIEZO1, a mechanosensitive cation channel, to be expressed in mouse and human Mks. Human mutations in PIEZO1 have been described to be associated with blood cell disorders. Yet, a role for PIEZO1 in megakaryopoiesis and proplatelet formation has never been investigated. Here, we show that activation of PIEZO1 increases the number of immature Mks in mice, while the number of mature Mks and Mk ploidy level are reduced. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Similarly, in human samples, PIEZO1 is expressed during megakaryopoiesis. Its activation reduces Mk size, ploidy, maturation, and proplatelet extension. Resulting effects of PIEZO1 activation on Mks resemble the profile in Primary Myelofibrosis (PMF). Intriguingly, Mks derived from Jak2V617F PMF mice show significantly elevated PIEZO1 expression, compared to wild‐type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2V617F PMF patients show increased PIEZO1 expression compared to Essential Thrombocythemia. Most importantly, PIEZO1 expression in bone marrow Mks is inversely correlated with patient platelet count. The ploidy, maturation, and proplatelet formation of Mks from JAK2V617F PMF patients are rescued upon PIEZO1 inhibition. Together, our data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation in PMF Mks might contribute to aggravating some hallmarks of the disease.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 98%

Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis

Abbonante,

Karkempetzaki,

Leon

et al. 2024

American J Hematol

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“…Thrombosis risk is often underestimated in MF, in particular for those in the so‐called lower prognostic groups with a JAK2 V617F mutation 5 . An individualised risk assessment is warranted.…”

Section: Clinical Featuresmentioning

confidence: 99%

Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline

McLornan,

Godfrey,

Green

et al. 2023

Br J Haematol

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This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015. 1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary myelofibrosis (PMF), as well as post-polycythaemia vera myelofibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the management of MF and is published alongside this guideline. M ETHODOLOGYThese guidelines were compiled according to the BSH process https:// b-s-h. org. uk/ media/ 16732/ bsh-guida nce-devel opmen tproce ss-dec-5-18. pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http:// www. grade worki nggro up. org. Recommendations are based on a review of the relevant MF-related literature using Medline, PubMed/Medline and Cochrane searches beginning from 2012 up to mid-2022. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. Exclusion criteria included papers published in non-English journals and those publications without an abstract.

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“…Recently, Mosquera-Orgueira et al derived and validated the Artificial Intelligence Prognostic Scoring System for Myelofibrosis model, which was based on eight clinical variables at diagnosis, by analyzing data from 1617 MF patients who were included in the Spanish Myelofibrosis Registry [ 81 ]. Barbui et al recently reported that PMF patients harboring JAK2 V617 in combination with lower IPSS scores had a higher risk of thrombosis [ 82 ].…”

Section: Molecular Profiles Of Mf Phenotypes and Prognosticationmentioning

confidence: 99%

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Chifotides

Verstovšek

Bose

2023

Cancers

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Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.

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Increased risk of thrombosis in JAK2 V617F-positive patients with primary myelofibrosis and interaction of the mutation with the IPSS score

Cited by 7 publications

References 9 publications

Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis

Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis

Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

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