Sabotaged Integral HSC Heterogeneity Underlies Essential Thrombocythemia Development

作者：Jingyuan Tong, Di Wang, Haoze Song, Ting Sun, Yanhong Zhao, Wenjing Gu, Lexuan Lin, Yitong Zhao, Yipeng Liang, Jin Xu, Rongfeng Fu, Mankai Ju, Jie Gao, Jinfa Ma, Chengjie Gao, Anqi Zhang, Zhijian Xiao, Erlie Jiang, Renchi Yang, Shihui Ma, Lei Zhang, Lihong Shi · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202505249 · 被引用次数：1 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Platelet Disorders and Treatments、Chronic Myeloid Leukemia Treatments

Abstract 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 V617F ‐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 + HSC subset is reduced across the ET spectrum. Loss of CXCR4 + 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.