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Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.

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.See related commentary by Savona and Rathmell, p. 831.This article is highlighted in the In This Issue feature, p. 813.

SUBMITTER: Chen X

PROVIDER: S-EPMC6606342 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.

Chen Xufeng X Glytsou Christina C Zhou Hua H Narang Sonali S Reyna Denis E DE Lopez Andrea A Sakellaropoulos Theodore T Gong Yixiao Y Kloetgen Andreas A Yap Yoon Sing YS Wang Eric E Gavathiotis Evripidis E Tsirigos Aristotelis A Tibes Raoul R Aifantis Iannis I

Cancer discovery 20190502 7

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 signif ...[more]

PMID: 31048321

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Project description:Simple Summary Venetoclax has proven to be a promising therapy for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Current ongoing clinical trials are evaluating its effectivity as frontline therapy for all acute myeloid leukemia (AML) patients. However, response rates vary wildly, depending on patient characteristics and mutational profiles. This review elaborates on the efficacy and safety of venetoclax compared to conventional chemotherapy for treatment of AML patients, comparing the response rates, overall survival and adverse events. Moreover, it gives an overview of genetic and epigenetic AML cell characteristics that give enhanced or decreased response to venetoclax and offers insights into the pathogenesis of venetoclax sensitivity and resistance. Additionally, it suggests possible treatment combinations predicted to be successful based on identified mechanisms influencing venetoclax sensitivity of AML cells. Abstract Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.

Dataset Information

Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.

Publications

Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.

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