BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL-1 are in clinical trials. Yet, resistance to single or combinatorial BH3 mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy and mitochondrial dynamics regulators sensitizes AML cells to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), which is essential in AML, while its protein levels positively correlate with drug resistance in patients with AML. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. Genetic or chemical targeting of MFN2, or global pharmacologic inhibition of autophagy, synergizes with BH3 mimetics and is a promising strategy to circumvent resistance in AML.

Citation Format: Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Evripidis Gavathiotis, Iannis Aifantis. Mitochondrial dynamics alterations in BH3 mimetics resistance in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A03.