Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms
Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms
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造血干细胞异质性与骨髓增殖性肿瘤的起始和治疗反应有关
DOI：
10.1016/j.stem.2021.01.018
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发表时间：
2021-03-04
期刊：
影响因子：
23.9
通讯作者：
Shi, Lihong
中科院分区：
文献类型：
--
作者：
Tong, Jingyuan;Sun, Ting;Shi, Lihong
干细胞异质性对疾病发病机制和治疗的影响尚不明确。JAK2V617F（+）骨髓增生性肿瘤（MPN）在造血干细胞（HSC）中具有相同的突变，表现出不同的表型，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。单细胞基因表达谱与平行突变检测表明，巨核细胞（Mk）致敏的HSC亚群在JAK2V617 F（+）ET未治疗的个体中显著扩增，并具有增强的潜力，主要由JAK2突变和干扰素信号升高驱动。在治疗期间，突变型HSC优先靶向Mk致敏的HSC亚群。有趣的是，纯合子突变型HSC被迫重新进入静止期，而它们的杂合子对应物经历凋亡。这项研究为干细胞异质性与恶性疾病的发病机制和治疗反应之间的联系提供了重要证据。
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 themegakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F(+) ET, driven primarily by the JAK2mutation 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.