Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.
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.See related commentary by Savona and Rathmell, p. 831.This article is highlighted in the In This Issue feature, p. 813.
Mesh Terms:
Animals, Antineoplastic Agents, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm, Endopeptidase Clp, GTP Phosphohydrolases, HEK293 Cells, HeLa Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Xenograft Model Antitumor Assays
Animals, Antineoplastic Agents, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm, Endopeptidase Clp, GTP Phosphohydrolases, HEK293 Cells, HeLa Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Xenograft Model Antitumor Assays
Cancer Discov
Date: Dec. 01, 2018
PubMed ID: 31048321
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