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Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development
Jingyuan Tong1, Di Wang1, Haoze Song1
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 21, 2025
Summary
Essential thrombocythemia (ET) involves distinct mutations affecting hematopoietic stem cells (HSCs). This study reveals how JAK2, CALR, and MPL mutations, and triple-negative ET, alter HSC function and contribute to disease, offering new therapeutic targets.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Essential thrombocythemia (ET) is characterized by JAK2, CALR, or MPL mutations, or is triple-negative (TN).
- The impact of specific driver mutations on hematopoietic stem cell (HSC) heterogeneity and ET pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the molecular features of HSCs across different ET subtypes using single-cell RNA sequencing.
- To elucidate the role of driver mutations and HSC subset alterations in ET pathogenesis.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of HSCs from ET patients.
- Detection of driver mutations (JAK2, CALR, MPL) within HSCs.
- Transcriptional profiling and comparative analysis of HSC subsets.
Main Results:
- MPL-mutated HSCs show aberrant metabolism; CALR-mutated HSCs exhibit active cell cycling.
- JAK2V617F-mutated HSCs display enhanced megakaryocyte (Mk) priming and interferon (IFN) response.
- A novel HSC subset in TN ET resembles driver-mutated HSCs; reduced CXCR4+ HSCs skew myeloid differentiation and accelerate ET onset.
Conclusions:
- Specific driver mutations confer distinct molecular characteristics to HSCs in ET.
- Altered HSC heterogeneity, particularly the loss of CXCR4+ HSCs, contributes to ET pathogenesis.
- Findings suggest potential therapeutic strategies targeting HSC dysfunction in ET.
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