Abstract
Typ515 (W515) mutations in the protein MPL are one of the key driver mutations promoting BCR-ABL-negative myeloproliferative neoplasms (MPNs), but, to our knowledge, 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–like (ET-like) MPN phenotype, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically, we observed that the MplW514L-conditioned HSC compartment had a unique disease-initiating capacity; however, it did not exhibit a obvious advantage of competitive repopulation over the WT 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 the MPLW515L mutation in HSCs and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.
Authors
Shujing Zhang, Jingjing Liu, Yuan Li, Yi Wang, Lingling Wang, Miaomiao Xu, Yanxia Li, Ge Dong, Shanshan Wang, Yanmei Li, Zhigang Cai, Baobing Zhao
Graphical abstract
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)