American Association for Cancer Research
Browse
- No file added yet -

Supplementary Methods from Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

Download (101.28 kB)
journal contribution
posted on 2024-09-16, 09:31 authored by 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

Supplementary Methods, Tables, and References

History

ARTICLE 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.

Usage metrics

    Cancer Discovery

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC