TitleASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.
Publication TypeJournal Article
Year of Publication2012
AuthorsAbdel-Wahab, Omar, Adli Mazhar, LaFave Lindsay M., Gao Jie, Hricik Todd, Shih Alan H., Pandey Suveg, Patel Jay P., Chung Young Rock, Koche Richard, Perna Fabiana, Zhao Xinyang, Taylor Jordan E., Park Christopher Y., Carroll Martin, Melnick Ari, Nimer Stephen D., Jaffe Jacob D., Aifantis Iannis, Bernstein Bradley E., and Levine Ross L.
JournalCancer Cell
Date Published2012 Aug 14
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

<p>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.</p>

Alternate JournalCancer Cell
PubMed ID22897849
PubMed Central IDPMC3422511
Grant ListU54 CA143798 / CA / NCI NIH HHS / United States
K08 CA160647 / CA / NCI NIH HHS / United States
R01 CA105129 / CA / NCI NIH HHS / United States
R01 CA169784 / CA / NCI NIH HHS / United States
1K08CA160647-01 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 CA173636 / CA / NCI NIH HHS / United States
5U01HL100395 / HL / NHLBI NIH HHS / United States