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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice

Leukemia volume 37, pages 1287–1297 (2023)Cite this article

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Abstract

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2P95H with Jak2V617F, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2P95H unexpectedly delayed myelofibrosis induced by Jak2V617F and decreased TGFβ1 serum level. Srsf2P95H reduced the competitiveness of transplanted Jak2V617F hematopoietic stem cells while preventing their exhaustion. RNA sequencing of sorted megakaryocytes identified an increased number of splicing events when the two mutations were combined. Focusing on JAK/STAT pathway, Jak2 exon 14 skipping was promoted by Srsf2P95H, an event detected in patients with JAK2V617F and SRSF2P95 co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2P95H delays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2 wild-type animals. These results unveil JAK2 exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions.

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Fig. 1: Co-mutation of Srsf2P95H delays Jak2V617F-induced myelofibrosis.
Fig. 2: Srsf2P95H co-mutation reduces Jak2V617F cell competitiveness.
Fig. 3: Impact of Srsf2P95H on Jak2V617F-induced megakaryocyte phenotypic modifications.
Fig. 4: Srsf2P95H co-mutation with Jak2V617F down-regulates genes involved in signaling pathways.
Fig. 5: Srsf2P95H promotes Jak2 exon 14 skipping.
Fig. 6: Srsf2P95H delays romiplositim-induced myelofibrosis.

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Data availability

Data are available in BioStudies under accession number: E-MTAB-11960.

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Acknowledgements

We thank the engineers and technicians of Gustave Roussy research facilities, including Laure Touchard, Mirile Ganga, Olivia Bawa, and Hélène Rocheteau, for valuable technical support, Richard Dyunga and Inge Snoeren (Erasmus University Rotterdam) for animal genotyping and nucleic acid extraction, respectively. ES group is supported by grants from the Institut National du Cancer (INCa) and Fondation ARC. The team is labeled by the Ligue Nationale Contre le Cancer (FP). CW received an MD/PhD track grant from the Philantropia Foundation. Funding to SNC is acknowledged from Ludwig Institute for Cancer Research, Fondation contre le cancer, Salus Sanguinis and Fondation “Les avions de Sébastien”, projets Action de recherché concertée (ARC) 16/21-073, Projet de recherche FNRS n°T.0043.21 and WelBio F 44/8/5—MCF/UIG—10955. IP, VW, CM and JLV received support from the MPN Reserch Foundation, INCa, and Ligue Nationale Contre le Cancer. TG and CB received PhD grants from the Ministry of Research and Higher Education and the Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France

    Christophe Willekens, Lucie Laplane, Tracy Dagher, Camelia Benlabiod, Catherine Lacout, Valérie Edmond, Valentine Marchand, Nathalie Droin, Florence Pasquier, Caroline Marty, Isabelle Plo, Jean-Luc Villeval, Françoise Porteu, William Vainchenker & Eric Solary

  2. Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France

    Christophe Willekens, Tracy Dagher, Camelia Benlabiod, Valentine Marchand, Nathalie Droin, Caroline Marty, Isabelle Plo, Jean-Luc Villeval, Françoise Porteu, William Vainchenker & Eric Solary

  3. Département d’hématologie, Gustave Roussy Cancer Campus, Villejuif, France

    Christophe Willekens, Florence Pasquier & Eric Solary

  4. Institut d’Histoire et Philosophie des Sciences et des Techniques, Université Paris I Panthéon-Sorbonne, Paris, France

    Lucie Laplane & Camelia Benlabiod

  5. Ludwig Institute for Cancer Research Brussels, Brussels, Belgium

    Nicolas Papadopoulos & Stefan N. Constantinescu

  6. Université catholique de Louvain and de Duve Institute, Brussels, Belgium

    Nicolas Papadopoulos & Stefan N. Constantinescu

  7. Gustave Roussy Cancer Campus, Villejuif, France

    Philippe Rameau, Cyril Catelain, Alexia Alfaro, Nicolas Signolle & Nathalie Droin

  8. Department of Hematology, Erasmus University, Rotterdam, The Netherlands

    Remco Hoogenboezem & Rebekka K. Schneider

  9. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany

    Rebekka K. Schneider

  10. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Alex Penson & Omar Abdel-Wahab

  11. Hematology department, Saint-Louis Hospital, Paris, France

    Stephane Giraudier

  12. WELBIO department, WEL Research Institute, Wavre, Belgium

    Stefan N. Constantinescu

  13. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, Oxford University, Oxford, UK

    Stefan N. Constantinescu

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Contributions

CW performed and supervised most of the experiments and contributed to the design of the study; TD, CB, NP, CL, PR, CC, VE, NS, AS, VM, ND, CM performed experiments; LL, AA, RH and AP realized bioinformatic analyses; JLV and OAW provided mouse models; SG and FP provided experimental human samples; CW, RS, JLV, OAW, CM, IP, SNC, FP and WV analysed the data; ES designed and supervised the study and wrote the paper. All authors approved the paper.

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Correspondence to Eric Solary.

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Willekens, C., Laplane, L., Dagher, T. et al. SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice. Leukemia 37, 1287–1297 (2023). https://doi.org/10.1038/s41375-023-01878-0

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