Medical College of Wisconsin
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Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc Natl Acad Sci U S A 2012 Mar 27;109(13):5028-33



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Pubmed Central ID





A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML.

Author List

Neff T, Sinha AU, Kluk MJ, Zhu N, Khattab MH, Stein L, Xie H, Orkin SH, Armstrong SA


Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Proliferation
Chromatin Immunoprecipitation
Disease Progression
Enhancer of Zeste Homolog 2 Protein
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Gene Silencing
Genes, Neoplasm
Genetic Loci
Histone-Lysine N-Methyltransferase
Mice, Inbred C57BL
Oncogene Proteins, Fusion
Polycomb Repressive Complex 2
Polycomb-Group Proteins
Precancerous Conditions
Proto-Oncogene Proteins c-myc
Repressor Proteins
jenkins-FCD Prod-468 69a93cef3257f26b866d455c1d2b2d0f28382f14