Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.

Abstract

Typ515 (W515) mutations in the protein MPL are one of key driver mutations promoting BCR/ABL-negative myeloproliferative neoplasms (MPNs), but their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia (ET)-like MPN phenotypes, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically we observed that MplW514L-conditioned HSC compartment had a unique disease-initiating capacity however it did not exhibit a obvious advantage of competitive repopulation over wild-type control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of MPLW515L mutation in HSCs, and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.