JAK2V617F-mutant vascular niche contributes to JAK2V617F clonal expansion in myeloproliferative neoplasms

Abstract

The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of blood cells. The acquired mutation JAK2^V617F plays a central role in these disorders. Mechanisms responsible for MPN HSPC expansion is not fully understood, limiting the effectiveness of current treatments. Endothelial cells (ECs) carrying the JAK2^V617F mutation can be detected in patients with MPNs, suggesting that ECs are involved in the pathogenesis of MPNs. Here we report that JAK2^V617F-bearing primary murine ECs have increased cell proliferation and angiogenesis in vitro compared to JAK2^WT ECs. While there was no difference between JAK2^V617F and JAK2^WT HSPC proliferation when co-cultured with JAK2^WT EC, the JAK2^V617F HSPC displayed a relative growth advantage over the JAK2^WT HSPC when co-cultured on JAK2^V617F EC. In addition, the thrombopoietin (TPO) receptor MPL is up regulated in JAK2^V617F ECs and contributes to the maintenance/expansion of the JAK2^V617F clone over JAK2^WT clone in vitro. Considering that ECs are an essential component of the hematopoietic niche and most HSPCs reside in the perivascular niche, our studies suggest that the JAK2^V617F-bearing ECs form an important component of the MPN vascular niche and contribute to mutant stem/progenitor cell expansion, likely through a critical role of the TPO/MPL signaling axis.

Keywords: Endothelial cells; Hematopoietic stem/progenitor cells; JAK2(V617F); MPL; Microenvironment; Myeloproliferative neoplasms.