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Updated: May 31, 2025
09:16
Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
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Mechanisms of enhancer-driven oncogene activation
Joyce Vriend1,2, Ruud Delwel1,2, Dorien Pastoors1,2
1Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
International Journal of Cancer
|January 24, 2025
Summary
Enhancer hijacking causes aggressive acute myeloid leukemia (AML) by increasing MECOM expression. Understanding enhancer deregulation is key to developing new AML treatments.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Aggressive acute myeloid leukemia (AML) subtypes are driven by enhancer hijacking, leading to MECOM overexpression.
- Chromosomal rearrangements like inv(3)/t(3;3) hijack the GATA2 enhancer, while other rearrangements involve different hematopoietic gene enhancers.
- BCL11B can hijack the same enhancers as MECOM, indicating broader roles for enhancer deregulation.
Purpose of the Study:
- To investigate the mechanisms of enhancer deregulation in AML.
- To explore the role of super-enhancers in oncogenesis.
- To identify potential therapeutic targets for AML and other cancers driven by enhancer deregulation.
Main Methods:
- Analysis of chromosomal rearrangements in AML.
- Investigation of enhancer activity and gene expression.
- Study of TAD boundary disruptions and de novo super-enhancer formation.
Main Results:
- Identified enhancer hijacking as a cause of MECOM overexpression in AML.
- Demonstrated that enhancers hijacked by MECOM can also be hijacked by BCL11B.
- Proposed that TAD boundary disruptions and super-enhancers may drive oncogenesis in AML without translocation-mediated enhancer hijacking.
Conclusions:
- Enhancer deregulation is a significant driver of oncogenesis in AML and other malignancies.
- Mechanistic insights into enhancer deregulation and super-enhancer activity are crucial for developing novel cancer therapies.
- Targeting enhancer deregulation offers a promising avenue for treating AML and related cancers.
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