RGD Reference Report - MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia. - Rat Genome Database

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MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia.

Authors: Riedel, SS  Haladyna, JN  Bezzant, M  Stevens, B  Pollyea, DA  Sinha, AU  Armstrong, SA  Wei, Q  Pollock, RM  Daigle, SR  Jordan, CT  Ernst, P  Neff, T  Bernt, KM 
Citation: Riedel SS, etal., J Clin Invest. 2016 Apr 1;126(4):1438-50. doi: 10.1172/JCI80825. Epub 2016 Feb 29.
RGD ID: 11530086
Pubmed: PMID:26927674   (View Abstract at PubMed)
PMCID: PMC4811120   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI80825   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
KMT2AHumanacute myeloid leukemia amelioratesISOKmt2a (Mus musculus) RGD 
Kmt2aMouseacute myeloid leukemia amelioratesIMP  RGD 
Kmt2aRatacute myeloid leukemia amelioratesISOKmt2a (Mus musculus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kmt2a  (lysine methyltransferase 2A)

Genes (Mus musculus)
Kmt2a  (lysine (K)-specific methyltransferase 2A)

Genes (Homo sapiens)
KMT2A  (lysine methyltransferase 2A)


Additional Information