Department of Pathology, NYU Langone Health and NYU School of Medicine, New York, New York.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and NYU School of Medicine, New York, New York.
Cancer Discov. 2019 Jul;9(7):890-909. doi: 10.1158/2159-8290.CD-19-0117. Epub 2019 May 2.
The BCL2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL2 inhibitor, has received FDA approval for the treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin . We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of venetoclax resistance, and its ablation sensitizes AML to venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent venetoclax resistance. SIGNIFICANCE: A genome-wide CRISPR/Cas9 screen reveals genes involved in mitochondrial biological processes participate in the acquisition of venetoclax resistance. Loss of the mitochondrial protein CLPB leads to structural and functional defects of mitochondria, hence sensitizing AML cells to apoptosis. Targeting CLPB synergizes with venetoclax and the venetoclax/azacitidine combination in AML in a p53-independent manner...
BCL2 家族在急性髓系白血病 (AML) 中发挥着重要作用。Venetoclax，一种选择性 BCL2 抑制剂，已获得 FDA 批准用于治疗 AML。然而，在长期治疗后会产生耐药性，这突显了需要更深入地了解潜在机制。在人类 AML 中，我们使用全基因组 CRISPR/Cas9 筛选鉴定了失活可使 AML 原始细胞对 Venetoclax 敏感的基因。在整个筛选过程中，涉及线粒体组织和功能的基因明显减少，包括线粒体伴侣蛋白. 我们证明 CLPB 在人类 AML 中上调，在获得 Venetoclax 耐药后进一步诱导，其缺失使 AML 对 Venetoclax 敏感。从机制上讲，CLPB 通过与嵴形成蛋白 OPA1 的相互作用维持线粒体嵴结构，而其缺失通过诱导嵴重塑和线粒体应激反应促进细胞凋亡。总的来说，我们的数据表明靶向线粒体结构可能是克服 Venetoclax 耐药的一种有前途的方法。意义：全基因组 CRISPR/Cas9 筛选揭示了参与线粒体生物学过程的基因参与 Venetoclax 耐药的获得。线粒体蛋白 CLPB 的缺失导致线粒体的结构和功能缺陷，从而使 AML 细胞易于凋亡。以 CLPB 为靶点与 Venetoclax 以及 Venetoclax/阿扎胞苷联合使用在不依赖 p53 的情况下协同作用于 AML。
