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Oncogene ; 32(7): 930-8, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-22469984

RESUMO

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.


Assuntos
Proliferação de Células , Genes ras/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Complexo Repressor Polycomb 2/fisiologia , Substituição de Aminoácidos , Animais , Ácido Aspártico/genética , Modelos Animais de Doenças , Glicina/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Mutação de Sentido Incorreto/fisiologia , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/fisiologia , Células Tumorais Cultivadas
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