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A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition
Yadira M Soto-Feliciano1, Francisco J Sánchez-Rivera2, Florian Perner3,4,5
1Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York.
Cancer Discovery
|October 20, 2022
Summary
Menin-MLL inhibitors disrupt leukemia survival by altering chromatin modifiers. Reactivating tumor suppressor genes with CDK4/6 inhibitors overcomes resistance to these leukemia treatments.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Oncology
- Chromatin Regulation
Background:
- Menin protein interacts with MLL1-fusion proteins, a target for leukemia treatment.
- Small molecule inhibitors targeting Menin-MLL interactions are in clinical trials for leukemia.
- Understanding resistance mechanisms to Menin-MLL inhibitors is crucial for effective leukemia therapy.
Purpose of the Study:
- To investigate the molecular mechanisms dictating response to Menin-MLL inhibitors in leukemia.
- To identify novel therapeutic strategies to overcome resistance to Menin-MLL inhibitors.
- To elucidate the role of chromatin-modifying complexes in leukemia survival and treatment response.
Main Methods:
- Integration of chromatin-focused and genome-wide CRISPR screens.
- Application of genetic, pharmacologic, and biochemical approaches.
- Utilized murine and human leukemia models.
Main Results:
- Discovered a molecular switch between MLL1-Menin and MLL3/4-UTX complexes that governs response to Menin-MLL inhibitors.
- MLL1-Menin complex impedes MLL3/4-UTX binding, maintaining leukemia cell survival.
- Disruption of Menin-MLL1 interaction activates a tumor-suppressive program via UTX, dictating therapeutic response.
- CDK4/6 inhibitors reactivate repressed tumor suppressor genes, mitigating resistance to Menin inhibitors in leukemia.
Conclusions:
- Menin-MLL and MLL3/4-UTX complexes play conserved roles in epigenetic regulation and leukemia.
- Therapeutic reactivation of tumor suppressor gene programs offers a strategy to overcome Menin inhibitor resistance.
- Findings provide insights into targeting epigenetic pathways for improved leukemia treatment outcomes in clinical trials.
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