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 JAK2V617F 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 JAK2V617F mutation can be detected in patients with MPNs, suggesting that ECs are involved in the pathogenesis of MPNs. Here we report that JAK2V617F-bearing primary murine ECs have increased cell proliferation and angiogenesis in vitro compared to JAK2WT ECs. While there was no difference between JAK2V617F and JAK2WT HSPC proliferation when co-cultured with JAK2WT EC, the JAK2V617F HSPC displayed a relative growth advantage over the JAK2WT HSPC when co-cultured on JAK2V617F EC. In addition, the thrombopoietin (TPO) receptor MPL is up regulated in JAK2V617F ECs and contributes to the maintenance/expansion of the JAK2V617F clone over JAK2WT 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 JAK2V617F-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.