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The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

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.

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Acknowledgements

We thank J Simon, E Earl and L Bianco for support with mouse work; S Hearn for microscopy support; G Hannon laboratory for support of shRNA screening methodology; and G Blobel for comments on the manuscript. CRV, JS, EW and MT were supported by the Don Monti Memorial Research Foundation, Laurie Strauss Leukemia Foundation, Sass Foundation, Edward P Evans Foundation and FM Kirby Foundation for research support. JZ was supported by a research fellowship from the German Research Foundation (DFG) and by the Andrew Seligson Memorial Clinical Fellowship at CSHL; ARR was supported by an NIH traineeship and the Barbara McClintock fellowship. SWL is supported by a Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society of America, a Cancer Target Discovery and Development (CTD2) grant from the National Cancer Institute and by the Howard Hughes Medical Institute.

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Correspondence to S W Lowe or C R Vakoc.

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Shi, J., Wang, E., Zuber, J. et al. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia. Oncogene 32, 930–938 (2013). https://doi.org/10.1038/onc.2012.110

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Keywords

  • chromatin
  • leukemia
  • epigenetics
  • MLL
  • PRC2

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