<i>JAK2V617F</i>-bearing vascular niche enhances malignant hematopoietic regeneration following radiation injury

Abstract

Myeloproliferative neoplasms are clonal stem cell disorders characterized by hematopoietic stem/progenitor cell expansion. The acquired kinase mutation <i>JAK2V617F</i> plays a central role in these disorders. Abnormalities of the marrow microenvironment are beginning to be recognized as an important factor in the development of myeloproliferative neoplasms. Endothelial cells are an essential component of the hematopoietic vascular niche. Endothelial cells carrying the <i>JAK2V617F</i> mutation can be detected in patients with myeloproliferative neoplasms, suggesting that the mutant vascular niche is involved in the pathogenesis of these disorders. Here, using a transgenic mouse expressing <i>JAK2V617F</i> specifically in all hematopoietic cells (including hematopoietic stem/progenitor cells) and endothelial cells, we show that the <i>JAK2V617F</i>-mutant hematopoietic stem/progenitor cells are relatively protected by the <i>JAK2V617F</i>-bearing vascular niche from an otherwise lethal dose of irradiation during conditioning for stem cell transplantation. Gene expression analysis revealed that chemokine (C-X-C motif) ligand 12, epidermal growth factor, and pleiotrophin are up-regulated in irradiated <i>JAK2V617F</i>-bearing endothelial cells compared to wild-type cells. Our findings suggest that the mutant vascular niche may contribute to the high incidence of disease relapse in patients with myeloproliferative neoplasms following allogeneic stem cell transplantation, the only curative treatment for these disorders.