title: The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) 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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.forename: A
authors.initials: A
authors.lastname: Rappaport
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.forename: C
authors.initials: C
authors.lastname: Johns
authors.forename: S W
authors.initials: SW
authors.lastname: Lowe
authors.forename: C R
authors.initials: CR
authors.lastname: Vakoc
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D011905:Genes, ras / Q000235:genetics*; D005998:Glycine / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020125:Mutation, Missense / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D063146:Polycomb-Group Proteins; C494163:Suz12 protein, mouse; D001224:Aspartic Acid; D063151:Polycomb Repressive Complex 2; D005998:Glycine