Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role of ILK in maintaining a requisite level of mitochondrial oxidative metabolism in highly purified, quiescent LSCs. Thus, these findings point to ILK as a critical survival mediator to TKIs and quiescent stem cells, offering an attractive therapeutic target and model for curative combination therapies in stem-cell-driven cancers.

由于持续存在TKI耐药性的白血病干细胞（LSC）群体，慢性髓细胞性白血病（CML）患者通常需要使用ABL1酪氨酸激酶抑制剂（TKI）进行终身治疗。从转录组分析中，我们显示整合素连接激酶（ILK），粘着斑的关键组成部分，在TKI无反应的患者细胞及其LSC中高度表达。ILK的遗传和药理学抑制作用会损害无反应患者细胞的存活，即使在存在保护性小生境细胞的情况下，也会使它们对TKI敏感。此外，ILK抑制作用可在体内和体外消除患者的TKI难治性LSC，但不能消除正常的HSC。RNA测序和功能验证研究表明，ILK在维持高度纯化的静态LSC中线粒体氧化代谢所需水平方面起着重要作用。因此，这些发现表明ILK是TKI和静态干细胞的关键生存介质，为干细胞驱动的癌症的联合治疗提供了有吸引力的治疗靶点和模型。