加拿大特里福克斯实验室Xiaoyan Jiang、Katharina Rothe等研究人员合作发现，整合素链接激酶介导静息CML干细胞对酪氨酸激酶抑制剂的耐药性。相关论文于2020年5月14日在线发表在《细胞—干细胞》上。

Author: Katharina Rothe, Artem Babaian, Naoto Nakamichi, Min Chen, Shawn C. Chafe, Akie Watanabe, Donna L. Forrest, Dixie L. Mager, Connie J. Eaves, Shoukat Dedhar, Xiaoyan Jiang

Issue&Volume: 2020-05-14

Abstract: Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population ofleukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linkedkinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsivepatient cells and their LSCs. Genetic and pharmacological inhibition of ILK impairedthe survival of nonresponder patient cells, sensitizing them to TKIs, even in thepresence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractoryLSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role ofILK in maintaining a requisite level of mitochondrial oxidative metabolism in highlypurified, quiescent LSCs. Thus, these findings point to ILK as a critical survivalmediator to TKIs and quiescent stem cells, offering an attractive therapeutic targetand model for curative combination therapies in stem-cell-driven cancers.

DOI: 10.1016/j.stem.2020.04.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30144-2