生物
XBP1型
干细胞
癌症研究
慢性粒细胞白血病
表观遗传学
细胞生物学
酪氨酸激酶
尼罗替尼
白血病
甲磺酸伊马替尼
造血
伊马替尼
髓系白血病
免疫学
遗传学
信号转导
RNA剪接
基因
核糖核酸
作者
Jingfeng Zhou,Shubo Wang,Danian Nie,Peilong Lai,Yiqing Li,Yangqiu Li,Yanli Jin,Jingxuan Pan
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-09-22
卷期号:13 (612)
被引量:15
标识
DOI:10.1126/scitranslmed.abh3462
摘要
Relapse of patients with chronic myelogenous leukemia (CML) may occur at least partially because leukemia stem cells (LSCs) lack sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib. The precise regulation of LSC stemness is incompletely understood. Given that traits of LSCs are subject to epigenetic regulation, we hypothesized that LSCs might be dependent on continuous active transcription of genes associated with super-enhancers (SEs), which might, in turn, suggest an opportunity for intervention. In this study, we tested this hypothesis and delineated the SE landscape in LSCs from patients with CML. Disruption of the SE-associated gene transcription by THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, efficiently eradicated LSCs in retroviral BCR-ABL–driven CML mice while sparing normal hematopoietic stem cells. Furthermore, we found that X-box binding protein 1 (XBP1), a substrate of mRNA-splicing endonuclease IRE1α in the unfolded protein response pathway, was an SE-associated oncogene in LSCs. Knockdown of XBP1 reduced survival and self-renewal capacity in primary CML CD34+ cells and eradicated LSCs in CML mice. Selectively blocking generation of the spliced form of Xbp1 by hematopoietic cell–specific Ire1 conditional knockout suppressed the progression of CML and impaired the leukemogenesis of LSCs in CML mice. Overall, we identified an epigenetic transcriptional program in LSCs, adding to evidence for the theory of “oncogene addiction” and suggesting a potential targeting strategy for CML.
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