Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F–positive MPNs in vivo Available to Purchase

• JAK2 V617F induces splenomegaly, erythrocytosis, leukocytosis, and perivascular fibrosis of the spleen in the absence of MPL.

• MPL is required for JAK2 V617F–dependent expansion of hematopoietic stem cells but not of early hematopoietic progenitors.

The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling through several type I cytokine receptors, namely the erythropoietin receptor, the thrombopoietin receptor (TpoR)/myeloproliferative leukemia (Mpl) protein, and the granulocyte colony-stimulating factor receptor. 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, in which 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 knockout background. Our findings indicate that erythrocytosis, leukocytosis, and moderate splenomegaly with mild perivascular fibrosis of the spleen 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, although 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.