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- Title
The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras<sup>G12D</sup> acute myeloid leukemia.
- Authors
Shi, J; Wang, E; Zuber, J; Rappaport, A; Taylor, M; Johns, C; Lowe, S W; Vakoc, C R
- Abstract
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.
- Publication
Oncogene, 2013, Vol 32, Issue 7, p930
- ISSN
0950-9232
- Publication type
Academic Journal
- DOI
10.1038/onc.2012.110