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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis

Leukemia volume 38, pages 1971–1984 (2024)Cite this article

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A Correction to this article was published on 01 April 2025

This article has been updated

Abstract

Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.

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Fig. 1: Biochemical pathways and functional biological processes associated with differentially expressed proteins in myelofibrosis.
Fig. 2: High thrombopoietin concentrations induce PF4 synthesis and release from megakaryocytes.
Fig. 3: PF4 induces a profibrotic phenotype in stimulated stromal cells.
Fig. 4: Cxcl4 knockdown in megakaryocytes mitigates the acquisition of an activated phenotype in co-cultured stromal cells.
Fig. 5: Glycosaminoglycans (GAGs) mediate PF4 uptake and profibrotic effects in stromal cells.
Fig. 6: In vivo pharmacological inhibition of GAGs prevents PF4-GAGs interaction, PF4 uptake and ameliorates fibrosis.
Fig. 7: PF4 is increased in MPN patients, correlates with fibrosis stage and co-localize with CSPG and stromal cells in patients with overt PMF.

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Data availability

Proteomic data have been deposited to the UNIMI Dataverse repository, accessible at: https://doi.org/10.13130/RD_UNIMI/RI3IDJ.

Change history

  • 27 March 2025

    The original online version of this article was revised: In this article the author’s name Niccolò Bartalucci was incorrectly written as Bartalucci Niccolò. The original article has been corrected.

  • 01 April 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41375-025-02587-6

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Acknowledgements

We thank Amgen Inc for providing Romiplostim-Nplate®; the animal facility and the OPBA of the University of Pavia for hosting the animals and support in animal protocol drawing up and the Unitech OMICs platform at the University of Milan for Orbitrap LC-MS/MS analysis. We thank Prof. Christian Di Buduo and Dr. Carolina Paula Miguel (University of Pavia) for technical assistance with confocal microscopy analysis. This paper was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG 2020 24541) to AM, (AIRC IG 2016 18700) to AB; Italian Ministry of University and Research (PRIN 2017-Z5LR5Z) to AB; Italian Ministry of Health (Ricerca Finalizzata Giovani Ricercatori GR-2016-02363136) to AM and VA, Cariplo Foundation (2018-0525) to AM.

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  1. These authors contributed equally: Daniele Capitanio, Francesca R. Calledda.

Authors and Affiliations

  1. Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

    Daniele Capitanio, Manuela Moriggi & Cecilia Gelfi

  2. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Francesca R. Calledda, Vittorio Abbonante, Alessandra Balduini & Alessandro Malara

  3. Department of Health Sciences, Magna Graecia University, Catanzaro, Italy

    Vittorio Abbonante

  4. Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Daniele Cattaneo, Cristina Bucelli & Alessandra Iurlo

  5. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Niccolò Bartalucci & Alessandro Maria Vannucchi

  6. Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Azienda Ospedaliera-Universitaria Careggi, Florence, Italy

    Niccolò Bartalucci & Alessandro Maria Vannucchi

  7. Department of Health Sciences, University of Milan, S.C. di Anatomia Patologica, ASST-Santi Paolo e Carlo, Milan, Italy

    Delfina Tosi & Umberto Gianelli

  8. IRCCS Orthopedic Institute Galeazzi, Milan, Italy

    Cecilia Gelfi

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Contributions

DCap, FRC performed experiments, collected, and analyzed data, and wrote the manuscript. VA and MM performed experiments, collected and analyzed data. CG conceived the study and provided intellectual input. DCat, CB and AI recruited and governed the patient’s ethics, performed experiments, analyzed data, and helped to draft the manuscript. NB and AMV provided specimens from JAK2floxed/+ and JAK2V617F/+ mice. UG interpreted the data and helped write the manuscript. DT helped with histopathological analyses. AB and AM conceived the study, interpreted the data and helped write the manuscript. All authors provided input on and reviewed the manuscript.

Corresponding authors

Correspondence to Alessandra Balduini or Alessandro Malara.

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Competing interests

AI is speaker honoraria from AOP Health, BMS, GSK, Incyte, Novartis and Pfizer. DC is speaker honoraria from BMS, GSK, Incyte, Novartis and Pfizer; the remaining authors declare no competing interests.

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The original online version of this article was revised: In this article the author’s name Niccolò Bartalucci was incorrectly written as Bartalucci Niccolò. The original article has been corrected.

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Capitanio, D., Calledda, F.R., Abbonante, V. et al. Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis. Leukemia 38, 1971–1984 (2024). https://doi.org/10.1038/s41375-024-02354-z

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