The JAK2V617F-bearing vascular niche promotes clonal expansion in myeloproliferative neoplasms

Abstract

The acquired kinase mutation JAK2V617F plays a central role in myeloproliferative neoplasms (MPNs). However, the mechanisms responsible for the malignant hematopoietic stem/progenitor cell (HSPC) expansion seen in patients with MPNs are not fully understood, limiting the effectiveness of current treatment. Endothelial cells (ECs) are an essential component of the hematopoietic niche, and they have been shown to express the JAK2V617F mutation in patients with MPNs. We show that the JAK2V617F-bearing vascular niche promotes the expansion of the JAK2V617F HSPCs in preference to JAK2WT HSPCs, potentially contributing to poor donor cell engraftment and disease relapse following stem cell transplantation. The expression of Chemokine (C-X-C motif) ligand 12 (CXCL12) and stem cell factor (SCF) were upregulated in JAK2V617F-bearing ECs compared to wild-type ECs, potentially accounting for this observation. We further identify that the thrombopoietin (TPO)/MPL signaling pathway is critical for the altered vascular niche function. A better understanding of how the vascular niche contributes to HSPC expansion and MPN development is essential for the design of more effective therapeutic strategies for patients with MPNs.