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Cancer Cell DOI:10.1016/j.ccr.2012.06.032

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

Publication TypeJournal Article
Year of Publication2012
AuthorsAbdel-Wahab, O, Adli, M, LaFave, LM, Gao, J, Hricik, T, Shih, AH, Pandey, S, Patel, JP, Chung, YRock, Koche, R, Perna, F, Zhao, X, Taylor, JE, Park, CY, Carroll, M, Melnick, A, Nimer, SD, Jaffe, JD, Aifantis, I, Bernstein, BE, Levine, RL
JournalCancer Cell
Volume22
Issue2
Pages180-93
Date Published2012 Aug 14
ISSN1878-3686
KeywordsAnimals, 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, ras Proteins, Repressor Proteins, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Up-Regulation
Abstract

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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1535-6108(12)00303-0
DOI10.1016/j.ccr.2012.06.032
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22897849?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID22897849
PubMed Central IDPMC3422511
Grant ListR01 CA173636 / CA / NCI NIH HHS / United States
5U01HL100395 / HL / NHLBI NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
K08 CA160647 / CA / NCI NIH HHS / United States
R01 CA105129 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 CA169784 / CA / NCI NIH HHS / United States
1K08CA160647-01 / CA / NCI NIH HHS / United States