Targeting mitochondrial structure sensitizes acute myeloid leukemia to Venetoclax treatment
Menée in vitro et à l'aide d'un modèle murin de leucémie myéloïde aiguë, cette étude met en évidence l'intérêt de cibler CLPB, une protéine impliquée dans le maintien de la structure des crêtes mitochondriales, pour sensibiliser les cellules cancéreuses au vénétoclax
The BCL-2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL-2 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.
Cancer Discovery 2019