Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Authors

Christina Glytsou
Xufeng Chen
Emmanouil Zacharioudakis
Wafa Al-Santli
Hua Zhou
Bettina Nadorp
Soobeom Lee
Audrey Lasry
Zhengxi Sun
Dimitrios Papaioannou
Michael Cammer
Kun Wang
Tomasz Zal
Malgorzata Anna Zal
Bing Z Carter
Jo Ishizawa
Raoul Tibes
Aristotelis Tsirigos
Michael Andreeff
Evripidis Gavathiotis
Iannis Aifantis

Publication Date

7-7-2023

Journal

Cancer Discovery

Abstract

BH3 mimetics are used as an efficient strategy to induce cell death in several blood 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. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.

Keywords

BH3-mimetics, resistance, mitophagy, MFN2, AML

Comments

Supplementary Materials

PMID: 37088914