Mechanism of BIM-induced ibrutinib resistance in chronic lymphocytic leukemia
加乐 张, 必慧 潘, 佳竹 吴, 祎琳 孔, 莉 王, 卫 徐
TL;DR
This study explores how reduced BIM protein leads to resistance to ibrutinib in chronic lymphocytic leukemia by activating protective autophagy.
Contribution
The study identifies BIM as a novel factor in ibrutinib resistance through its role in autophagy activation in CLL.
Findings
BIM expression is significantly reduced in CLL drug-resistant cells and patient samples.
Knocking down BIM inhibits ibrutinib-induced apoptosis in CLL cells.
BIM suppression activates protective autophagy, contributing to drug resistance.
Abstract
探究BCL2家族蛋白BIM在慢性淋巴细胞白血病（CLL）伊布替尼耐药中的作用，分析其对凋亡和自噬的调控机制。 通过RNA测序检测CLL患者样本、CLL细胞株（MEC1细胞株）和耐药细胞株（MR）中BCL2家族表达变化。蛋白印迹法分析药物敏感细胞株凋亡时BIM蛋白表达变化，并用shRNA敲低BIM探讨其对增殖和凋亡的影响。利用RNA测序和自噬抑制剂氯喹观察MR自噬水平变化。 CLL原代细胞及MEC1细胞株耐药前后，BIM表达显著下调（P<0.0001）。在CLL细胞中敲低BIM可抑制由伊布替尼诱导的细胞凋亡（均P<0.05）。此外，在MR中可以观察到保护性自噬水平的提高，通过氯喹及小干扰RNA抑制自噬反应后可促进细胞凋亡。BIM敲低细胞株中LC3-Ⅱ蛋白表达增加（P<0.01），提示BIM降低可介导自噬激活。 BIM低表达是CLL中伊布替尼耐药的重要因素，其通过激活保护性自噬促进耐药，这为改善CLL治疗提供了新靶点。
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Taxonomy
TopicsChronic Lymphocytic Leukemia Research · Galectins and Cancer Biology · Lymphoma Diagnosis and Treatment