MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia.
Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expr...
| Publicado en: | Journal of Clinical Investigation Vol. 126; no. 4; pp. 1438 - 1451 |
|---|---|
| Autores principales: | , , , , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
American Society for Clinical Investigation
Apr2016
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=114199680&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 114199680 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00219738 0YX jtl: Journal of Clinical Investigation issn: 00219738 maglogo: N pubinfo: dt: Apr2016 vid: 126 iid: 4 pid: 11983 pub: American Society for Clinical Investigation place: Ann Arbor, Michigan artinfo: ui: 114199680 114199680 NLM26927674 10.1172/JCI80825 NLM26927674 PMC4811120 114199680 ppf: 1438 ppct: 13 formats: tig: atl: MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia. aug: au: Riedel, Simone S. Haladyna, Jessica N. Bezzant, Matthew Stevens, Brett Pollyea, Daniel A. Sinha, Amit U. Armstrong, Scott A. Qi Wei Pollock, Roy M. Daigle, Scott R. Jordan, Craig T. Ernst, Patricia Neff, Tobias Bernt, Kathrin M. Wei, Qi affil: Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA sug: subj: Leukemia, Myeloid, Acute Metabolism Transferases Metabolism Proteins Metabolism Male Proteins Female Transferases Mice Animals Leukemia, Myeloid, Acute Pathology Leukemia, Myeloid, Acute Scales Male Female ab: Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|