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Oncogene ; 32(7): 930-8, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-22469984

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.


Subject(s)
Cell Proliferation , Genes, ras/genetics , Leukemia, Myeloid, Acute/genetics , Oncogene Proteins, Fusion/genetics , Polycomb Repressive Complex 2/physiology , Amino Acid Substitution , Animals , Aspartic Acid/genetics , Disease Models, Animal , Glycine/genetics , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Transgenic , Models, Biological , Mutation, Missense/physiology , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Polycomb-Group Proteins/genetics , Polycomb-Group Proteins/physiology , Tumor Cells, Cultured
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