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

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. Published by Elsevier Inc.