The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia

• Published in: Oncogene Vol. 32; no. 7; p. 930
• Main Authors: Shi, J, Wang, E, Zuber, J, Rappaport, A, Taylor, M, Johns, C, Lowe, S W, Vakoc, C R
• Format: Journal Article
• Language: English
• Published: England 14.02.2013
• Subjects: Amino Acid Substitution; Animals; Aspartic Acid - genetics; Cell Proliferation; Disease Models, Animal; Genes, ras - genetics; Glycine - genetics; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Transgenic; Models, Biological; Mutation, Missense - physiology; Oncogene Proteins, Fusion - genetics; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Polycomb Repressive Complex 2 - physiology; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - physiology; Tumor Cells, Cultured
• ISSN: 1476-5594
• DOI: 10.1038/onc.2012.110

The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer.