Targeting mitochondrial structure sensitizes acute myeloid Leukemia to venetoclax treatment

Xufeng Chen, Christina Glytsou, Hua Zhou, Sonali Narang, Denis E. Reyna, Andrea Lopez, Theodore Sakellaropoulos, Yixiao Gong, Andreas Kloetgen, Yoon Sing Yap, Eric Wang, Evripidis Gavathiotis, Aristotelis Tsirigos, Raoul Tibes, Iannis Aifantis

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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 CLPB. 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.

Original languageEnglish (US)
Pages (from-to)890-909
Number of pages20
JournalCancer discovery
Volume9
Issue number7
DOIs
StatePublished - Jul 2019

ASJC Scopus subject areas

  • Oncology

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    Chen, X., Glytsou, C., Zhou, H., Narang, S., Reyna, D. E., Lopez, A., Sakellaropoulos, T., Gong, Y., Kloetgen, A., Yap, Y. S., Wang, E., Gavathiotis, E., Tsirigos, A., Tibes, R., & Aifantis, I. (2019). Targeting mitochondrial structure sensitizes acute myeloid Leukemia to venetoclax treatment. Cancer discovery, 9(7), 890-909. https://doi.org/10.1158/2159-8290.CD-19-0117