2. Academic Validation
  3. Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

  • Cancer Discov. 2023 Apr 24;CD-22-0601. doi: 10.1158/2159-8290.CD-22-0601.
Christina Glytsou 1,  Xufeng Chen 2,  Emmanouil Zacharioudakis 3,  Wafa Al-Santli 4,  Hua Zhou 5,  Bettina Nadorp 4,  Soobeom Lee 6,  Audrey Lasry 1,  Zhengxi Sun 1,  Dimitrios Papaioannou 7,  Michael Cammer 8,  Kun Wang 4,  Tomasz Zal 9,  Malgorzata Anna Zal 10,  Bing Z Carter 11,  Jo Ishizawa 12,  Raoul Tibes 13,  Aristotelis Tsirigos 14,  Michael Andreeff 11,  Evripidis Gavathiotis 15,  Iannis Aifantis 16
Affiliations

Affiliations

  • 1 New York University School of Medicine, New York, United States.
  • 2 New York University School of Medicine, New York, NY, United States.
  • 3 Albert Einstein College of Medicine, United States.
  • 4 New York University School of Medicine, United States.
  • 5 NYU Langone Health and School of Medicine, New York, United States.
  • 6 New York University, United States.
  • 7 New York University, New York, United States.
  • 8 New York University Grossman School of Medicine, Langone Medical Center, New York, NY, United States.
  • 9 The University of Texas MD Anderson Cancer Center, houston, United States.
  • 10 The University of Texas MD Anderson Cancer Center, United States.
  • 11 The University of Texas MD Anderson Cancer Center, Houston, Tx, United States.
  • 12 The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 13 AstraZeneca (United Kingdom), Cambridge, United Kingdom.
  • 14 NYU Langone Medical Center, New York, NY, United States.
  • 15 Albert Einstein College of Medicine, New York, United States.
  • 16 New York University Grossman School of Medicine, New York, NY, United States.
PMID: 37088914 DOI: 10.1158/2159-8290.CD-22-0601
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, Mcl-1 or dual Bcl-2/Bcl-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics 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 pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing Apoptosis in AML.

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