Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F- positive MPNs in vivo

Journal article

The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling of several type I cytokine receptors, namely those for erythropoietin (EpoR), thrombopoietin (TpoR), and Granulocyte Colony Stimulating Factor (G-CSFR). Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/MPL absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, where regulation of Jak2 expression does not depend on its natural promoter. In this study, we use a novel mouse model expressing Jak2 V617F under its endogenous promoter at the heterozygous state within a Mpl knock-out background. Our findings indicate that erythrocytosis, leukocytosis and moderate splenomegaly with mild spleen peri-vascular fibrosis persist even in the absence of Mpl expression. Notably, the inherent growth-stimulating effect induced by Jak2 V617F remains consistent across diverse early hematopoietic progenitor populations in the absence of Mpl but is reduced at the stem cell level and does not allow clonal expansion in competitive transplantation. Our results delineate Mpl-dependent and -independent phenotypes induced by Jak2 V617F and confirm that inhibiting Mpl expression at the stem cell level negates the long-term advantage of the mutant clone. Consequently, while MPL emerges as a major player in Jak2 V617F positive MPNs, our study underscores that it is not the exclusive contributor, broadening the spectrum for therapeutic intervention.

Authors: Papadopoulos, N; Nédélec, A; Rahmani, Y; Ryou, H; Defour, J-P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society of Hematology
• Journal: Blood
• Place of publication: United States
• Publication date: 2025-05-07
• Acceptance date: 2025-04-04
• DOI: 10.1182/blood.2024026711
• EISSN: 1528-0020
• ISSN: 0006-4971
• Pmid: 40332017
• Language: English
• Keywords: mouse model; Jak2 V617F; thrombopoietin receptor; myeloproliferative neoplasms; polycythemia vera