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.

中文翻译：

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超级增强剂景观揭示白血病干细胞对 X-box 结合蛋白 1 的依赖是一种治疗脆弱性

慢性粒细胞性白血病 (CML) 患者的复发可能至少部分是因为白血病干细胞 (LSC) 对伊马替尼等酪氨酸激酶抑制剂 (TKI) 缺乏敏感性。LSC 干性的精确调节尚不完全清楚。鉴于 LSC 的性状受表观遗传调控，我们假设 LSC 可能依赖于与超级增强子 (SE) 相关的基因的持续活跃转录，这反过来可能暗示干预的机会。在这项研究中，我们检验了这一假设并描绘了 CML 患者 LSC 中的 SE 格局。共价细胞周期蛋白依赖性激酶 7 (CDK7) 抑制剂 THZ1 破坏 SE 相关基因转录，有效根除逆转录病毒 BCR-ABL 驱动的 CML 小鼠中的 LSC，同时保留正常的造血干细胞。XBP1 ) 是未折叠蛋白反应通路中 mRNA 剪接内切酶 IRE1α 的底物，是 LSC 中的 SE 相关癌基因。XBP1的敲低降低了原代 CML CD34 ⁺细胞的存活率和自我更新能力，并根除 CML 小鼠中的 LSC。通过造血细胞特异性Ire1条件性敲除选择性阻断 Xbp1 的剪接形式的产生抑制了 CML 的进展并损害了 CML 小鼠中 LSC 的白血病发生。总体而言，我们在 LSC 中发现了一个表观遗传转录程序，为“癌基因成瘾”理论增加了证据，并提出了 CML 的潜在靶向策略。