Deletion of Stat2 in a Jak2V617F mouse model of MPN : impact on the phenotype and on the hematologic and molecular response to interferon-α

Myeloproliferative neoplasms are clonal hematopoietic disorders driven by mutations that induce constitutive activation of the JAK2/STAT signaling pathway, the most prevalent being the JAK2V617F mutation. Murine models of JAK2V617F-induced disease have provided tools for the preclinical testing of new therapies. Among these, treatment with interferon alpha induces significant hematologic and molecular responses, targeting the mutated clone via an undefined mechanism. STAT2 activation is the hallmark of the IFN-α signaling pathway. This work addresses the role of STAT2 in the MPN phenotype induced by JAK2V617F knock-in and the response to IFN-α therapy. We have shown that STAT2 acts as a brake on the MPN phenotype, mainly on the erythroid lineage and fibrosis features. Our work also revealed an unexpected role of STAT2 in the expression of STAT5 target genes and in the fitness of HSC. Finally, we demonstrated that IFN-α action required STAT2.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202