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ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.

Cancer cell | Aug 14, 2012

Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.

Pubmed ID: 22897849 RIS Download

Mesh terms: Animals | Cell Line, Tumor | Cell Proliferation | Cell Transformation, Neoplastic | DNA-Binding Proteins | Enhancer of Zeste Homolog 2 Protein | Gene Expression Regulation, Neoplastic | Gene Knockdown Techniques | Gene Silencing | Hematopoietic System | Histones | Homeodomain Proteins | Humans | Leukemia, Myeloid, Acute | Methylation | Mice | Mutation | Myeloid Cells | Polycomb Repressive Complex 2 | Polycomb-Group Proteins | Protein Binding | Repressor Proteins | Transcription Factors | Tumor Suppressor Proteins | Ubiquitin Thiolesterase | Up-Regulation | ras Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA173636
  • Agency: NHLBI NIH HHS, Id: 5U01HL100395
  • Agency: NCI NIH HHS, Id: U54 CA143798
  • Agency: NCI NIH HHS, Id: K08 CA160647
  • Agency: NCI NIH HHS, Id: R01 CA105129
  • Agency: Howard Hughes Medical Institute, Id: R01 CA169784
  • Agency: NCI NIH HHS, Id: 1K08CA160647-01
  • Agency: NCI NIH HHS, Id:

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