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Updated: May 24, 2026
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Investigation of Genetic Dependencies Using CRISPR-Cas9-based Competition Assays
Published on: January 7, 2019
Polycomb repressive complex 2 is required for MLL-AF9 leukemia
Tobias Neff1, Amit U Sinha, Michael J Kluk
1Dana-Farber/Children's Hospital Cancer Center, Boston, MA 02115, USA.
Summary
Polycomb repressive complex 2 (PRC2) plays a role in acute myeloid leukemia (AML) progression. While not essential for initial leukemia growth, inhibiting Ezh2 impacts AML progression and gene expression, suggesting therapeutic potential.
Area of Science:
- Epigenetics
- Cancer Biology
- Hematology
Background:
- Epigenetic mechanisms, including Polycomb repressive complex 2 (PRC2), are increasingly recognized for their role in cancer.
- PRC2 components are overexpressed in many cancers, but their precise function in cancer development and progression is not fully understood.
Purpose of the Study:
- To investigate the role of PRC2 function in leukemia development and progression using conditional alleles for enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed).
Main Methods:
- Conditional knockout alleles for Ezh2 and Eed were used in MLL-AF9-mediated acute myeloid leukemia (AML) models.
- Leukemia progression was assessed via secondary transplantation assays.
- Genome-wide analyses of H3K27me3 and gene expression arrays were performed.
Main Results:
- Ezh2-null AML showed impaired acceleration upon secondary transplantation but retained self-renewal capacity.
- Partial compensation of Ezh2 loss by Ezh1 was observed, indicated by locus-specific H3K27me3 persistence.
- Inactivation of Eed led to complete PRC2 loss and was incompatible with leukemia growth, causing more profound gene expression changes than Ezh2 inactivation.
Conclusions:
- Ezh2 is not strictly required for MLL-AF9 AML initiation but contributes to leukemia progression.
- Eed is essential for PRC2 function and leukemia viability.
- Targeting PRC2 function presents a potential therapeutic strategy for AML.
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