Abstract
Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) that are most frequently caused by acquired somatic mutations in JAK2. A number of conditional mouse models of JAK2-V617F-driven MPN have been generated that rely on Cre-LoxP-mediated activation, resulting in polyclonal disease. To more closely mimic the monoclonal origin of human MPN, transplantations of single purified JAK2-mutant HSCs or bone marrow (BM) at limiting dilutions into lethally irradiated recipient mice have been previously performed. However, irradiation is known to alter the BM microenvironment and also to induce transient aplasia accompanied by elevated cytokine levels that promote the expansion of the mutant clone. To overcome these limitations, we examined whether JAK2-V617F-mutant HSCs are able to engraft and initiate MPN in non-conditioned recipients. We found that BM from two different MPN models, one expressing the human JAK2-V617F, and another expressing the mouse Jak2-V617F, efficiently engrafted and initiated MPN in non-irradiated immunocompromised Rag2 (-/-) recipients. MPN evolved even in transplantations at limiting dilutions, showing the high competitiveness of single JAK2-mutant HSCs. In contrast, BM from mice expressing the human JAK2-V617F failed to engraft in non-conditioned immunocompetent C57BL/6 mice, while BM from mice expressing the mouse Jak2-V617F engrafted and initiated MPN, suggesting that mouse JAK2-V617F protein, which differs from the endogenous JAK2 in only one amino acid, was tolerated. Our results show that JAK2-V617F mutant HSCs can outcompete resident non-mutated HSCs even in the absence of elevated cytokine levels and without the need of emptying stem cell niches by irradiation.