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
  • 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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