中国医学科学院血液学研究所石莉红等研究人员合作发现，造血干细胞异质性与骨髓增生性肿瘤的起始和治疗反应有关。2021年2月22日，《细胞—干细胞》杂志在线发表了这一最新研究成果。

研究人员表示，干细胞异质性对疾病的发病机理和治疗的意义尚不明确。JAK2 V617F⁺骨髓增生性肿瘤（MPN）在造血干细胞（HSC）中具有相同的突变，并显示出多种表型，包括真性红细胞增多症（PV）、原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）。这些慢性恶性疾病是分析干细胞异质性病理后果的理想模型。

研究人员通过具有并行突变检测的单细胞基因表达谱分析发现，在未经治疗的JAK2 V617F⁺ET个体中，以巨核细胞（Mk）为主的HSC亚群显著扩增并具有增强的潜能，这主要是由JAK2突变和干扰素信号转导驱动的。在治疗过程中，突变HSC优先靶向Mk启动的HSC亚群。有趣的是，纯合突变HSC被迫重新进入静止状态，而它们的杂合对应物则发生凋亡。这项研究为干细胞异质性与恶性疾病的发病机理和治疗反应之间的联系提供了重要证据。 

附：英文原文

Title: Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms

Author: Jingyuan Tong, Ting Sun, Shihui Ma, Yanhong Zhao, Mankai Ju, Yuchen Gao, Ping Zhu, Puwen Tan, Rongfeng Fu, Anqi Zhang, Ding Wang, Di Wang, Zhijian Xiao, Jiaxi Zhou, Renchi Yang, Stephen J. Loughran, Juan Li, Anthony R. Green, Emery H. Bresnick, Dong Wang, Tao Cheng, Lei Zhang, Lihong Shi

Issue&Volume: 2021-02-22

Abstract: The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F+ myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F+ ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.

DOI: 10.1016/j.stem.2021.01.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00018-7