Shi, J., Wang, E., Zuber, J., Rappaport, A., Taylor, M., Johns, C., Lowe, S. W., Vakoc, C. R. (2013) The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia. Oncogene, 32 (7). pp. 930-938. ISSN 1476-5594 (Electronic)0950-9232 (Linking)
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.Oncogene advance online publication, 2 April 2012; doi:10.1038/onc.2012.110.
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