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Focus Formation: A Cell-based Assay to Determine the Oncogenic Potential of a Gene
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Selective Enhancer Gain-of-Function Deregulates MYC Expression in Multiple Myeloma
Mahshid Rahmat1,2, Kendell Clement2,3, Jean-Baptiste Alberge1,2,4
1Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Research
|September 23, 2024
Summary
Researchers discovered a new epigenetic mechanism driving MYC gene overexpression in multiple myeloma. This involves increased accessibility of a specific enhancer, leading to higher MYC expression and disease progression, offering potential new therapeutic targets.
Area of Science:
- Hematology
- Molecular Biology
- Epigenetics
Background:
- MYC deregulation is common in multiple myeloma, correlating with poor prognosis.
- Known drivers (translocations, amplifications) explain only ~40% of MYC overexpression cases.
Purpose of the Study:
- To investigate epigenetic mechanisms of MYC regulation in multiple myeloma.
- To identify novel drivers of MYC overexpression beyond genetic aberrations.
Main Methods:
- CRISPR interference (CRISPRi) was employed to assess enhancer activity.
- Analysis of transcription factor binding (cMAF, IRF4, SPIB) and enhancer accessibility.
- Investigation of focal amplification events at the enhancer region.
Main Results:
- An epigenetic mechanism involving increased plasma cell enhancer accessibility was identified, leading to MYC overexpression.
- This enhancer activity was independent of enhancer hijacking but driven by transcription factors cMAF, IRF4, and SPIB.
- Focal amplification of this enhancer occurred in ~3.4% of multiple myeloma patients.
Conclusions:
- A novel epigenetic pathway for MYC deregulation in multiple myeloma has been elucidated.
- Noncoding regulatory elements and transcription factor networks are critical drivers of multiple myeloma.
- This enhancer may serve as a predictive biomarker and therapeutic target for improving patient outcomes.
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