Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development
Essential thrombocythemia (ET) includes the JAK2 -, CALR-, and MPL-mutated subtypes, and a triple-negative (TN) ET subtype, which lacks these canonical drivers. How specific driver mutations affect hematopoietic stem cell (HSC) heterogeneity and their relation to ET pathogenesis remain unclear. Here, by using single-cell RNA sequencing (scRNA-seq) combined with driver mutation detection across ET patients, it is found that MPL-mutated HSCs exhibited aberrant metabolism, CALR-mutated HSCs displayed active cell cycling, while JAK2 <sup>V617F</sup>-mutated HSCs demonstrated enhanced megakaryocyte (Mk) priming capacity and interferon (IFN) response. An HSC subset is identified in TN ET that transcriptionally resembled driver-mutated HSCs, exhibiting enhanced megakaryocytic priming and proliferative activity. Notably, the frequency of a CXCR4<sup>+</sup> HSC subset is reduced across the ET spectrum. Loss of CXCR4<sup>+</sup> HSCs skewed lineage differentiation of HSCs toward the myeloid lineage, whereas restoring this subset delayed the onset of ET. Altogether, this study reveals both the shared and distinct molecular features of mutant HSCs in ET and provides novel insights into the pathogenesis and potential therapeutic strategies of ET.
Authors
- Jie Gao (ORCID: https://orcid.org/0000-0002-4648-7956)
- Haoze Song (ORCID: https://orcid.org/0009-0000-5952-5168)
- Erlie Jiang (ORCID: https://orcid.org/0000-0003-0237-6063)
- Chengjie Gao (ORCID: https://orcid.org/0009-0002-7453-7743)
- Jinfa Ma (ORCID: https://orcid.org/0000-0002-2119-8779)
- Renchi Yang (ORCID: https://orcid.org/0000-0003-3741-8518)
- Yipeng Liang (ORCID: https://orcid.org/0000-0003-1664-7864)
- Zhijian Xiao (ORCID: https://orcid.org/0000-0002-1099-4489)
- Wenjing Gu (ORCID: https://orcid.org/0000-0003-1604-7666)
- Yitong Zhao (ORCID: https://orcid.org/0000-0002-0086-2386)
- Lihong Shi (ORCID: https://orcid.org/0000-0001-8876-0802)
- Ting Sun (ORCID: https://orcid.org/0000-0002-2486-6146)
- Mankai Ju (ORCID: https://orcid.org/0000-0002-8784-9116)
- Rongfeng Fu (ORCID: https://orcid.org/0000-0001-5442-1028)
- Anqi Zhang (ORCID: https://orcid.org/0000-0001-5128-2464)
- Di Wang (ORCID: https://orcid.org/0000-0002-8904-2981)
- Jin Xu (ORCID: https://orcid.org/0000-0002-4964-9404)
- Lei Zhang (ORCID: https://orcid.org/0000-0001-7769-7377)
- Yanhong Zhao
- Lexuan Lin
- Jingyuan Tong
- Shihui Ma
Institutions
- Tianjin University of Technology (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Institute of Hematology & Blood Diseases Hospital (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1002/advs.202505249
- Citations
- 1
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- World Health Organization
- Tianjin Municipal Health Commission
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Chinese Academy of Medical Sciences
- Tianjin Science and Technology Committee
- Peking Union Medical College
- National Science and Technology Major Project
- Beijing Institute of Genomics, Chinese Academy of Sciences
- Bijzonder Onderzoeksfonds UGent
- National Key Research and Development Program of China