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

Shujing Zhang; Jingjing Liu; yuan li; Yi Wang; Lingling Wang; Miaomiao Xu; Yanxia Li; Ge Dong; Shanshan Wang; Yanmei Li; Zhigang Cai; Baobing Zhao

doi:10.1172/JCI199690

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Zhang, S. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Liu, J. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by li, y. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Wang, Y. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Wang, L. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Xu, M. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Li, Y. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Dong, G. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Wang, S. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Li, Y. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Cai, Z. in: PubMed | Google Scholar

¹State Key Laboratory of Discovery and Utilization of Functional Components , Shandong University, Jinan, China

²State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China

³The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China

Find articles by Zhao, B. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI199690.
Copyright © 2026, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 23, 2026 - Version history

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.

Version 1 (April 23, 2026): In-Press Preview

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

Shujing Zhang,¹ Jingjing Liu,² yuan li,¹ Yi Wang,¹ Lingling Wang,¹ Miaomiao Xu,¹ Yanxia Li,¹ Ge Dong,² Shanshan Wang,² Yanmei Li,³ Zhigang Cai,² and Baobing Zhao¹

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

Shujing Zhang,1 Jingjing Liu,2 yuan li,1 Yi Wang,1 Lingling Wang,1 Miaomiao Xu,1 Yanxia Li,1 Ge Dong,2 Shanshan Wang,2 Yanmei Li,3 Zhigang Cai,2 and Baobing Zhao1

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Shujing Zhang,¹ Jingjing Liu,² yuan li,¹ Yi Wang,¹ Lingling Wang,¹ Miaomiao Xu,¹ Yanxia Li,¹ Ge Dong,² Shanshan Wang,² Yanmei Li,³ Zhigang Cai,² and Baobing Zhao¹