TY - JOUR
T1 - Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia
AU - Glytsou, Christina
AU - Chen, Xufeng
AU - Zacharioudakis, Emmanouil
AU - Al-Santli, Wafa
AU - Zhou, Hua
AU - Nadorp, Bettina
AU - Lee, Soobeom
AU - Lasry, Audrey
AU - Sun, Zhengxi
AU - Papaioannou, Dimitrios
AU - Cammer, Michael
AU - Wang, Kun
AU - Zal, Tomasz
AU - Zal, Malgorzata Anna
AU - Carter, Bing Z.
AU - Ishizawa, Jo
AU - Tibes, Raoul
AU - Tsirigos, Aristotelis
AU - Andreeff, Michael
AU - Gavathiotis, Evripidis
AU - Aifantis, Iannis
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/7
Y1 - 2023/7
N2 - 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. SIGNIFICANCE: AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML.
AB - 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. SIGNIFICANCE: AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML.
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U2 - 10.1158/2159-8290.CD-22-0601
DO - 10.1158/2159-8290.CD-22-0601
M3 - Article
C2 - 37088914
AN - SCOPUS:85164267492
SN - 2159-8274
VL - 13
SP - 1656
EP - 1677
JO - Cancer discovery
JF - Cancer discovery
IS - 7
ER -
