1. SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice
- Author
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Willekens, Christophe, Laplane, Lucie, Dagher, Tracy, Benlabiod, Camelia, Papadopoulos, Nicolas, Lacout, Catherine, Rameau, Philippe, Catelain, Cyril, Alfaro, Alexia, Edmond, Valérie, Signolle, Nicolas, Marchand, Valentine, Droin, Nathalie, Hoogenboezem, Remco, Schneider, Rebekka K., Penson, Alex, Abdel-Wahab, Omar, Giraudier, Stephane, Pasquier, Florence, Marty, Caroline, Plo, Isabelle, Villeval, Jean-Luc, Constantinescu, Stefan N., Porteu, Françoise, Vainchenker, William, and Solary, Eric
- 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 Srsf2P95Hwith Jak2V617F, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl)gene promoter. In transplantation experiments, Srsf2P95Hunexpectedly delayed myelofibrosis induced by Jak2V617Fand decreased TGFβ1 serum level. Srsf2P95Hreduced the competitiveness of transplanted Jak2V617Fhematopoietic 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, Jak2exon 14 skipping was promoted by Srsf2P95H, an event detected in patients with JAK2V617Fand SRSF2P95co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2P95Hdelays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2wild-type animals. These results unveil JAK2exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions.
- Published
- 2023
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