RGD Reference Report - Menin is necessary for long term maintenance of meningioma-1 driven leukemia. - Rat Genome Database

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Menin is necessary for long term maintenance of meningioma-1 driven leukemia.

Authors: Libbrecht, Clara  Xie, Hongbo M  Kingsley, Molly C  Haladyna, Jessica N  Riedel, Simone S  Alikarami, Fatemeh  Lenard, Alexandra  McGeehan, Gerard M  Ernst, Patricia  Bernt, Kathrin M 
Citation: Libbrecht C, etal., Leukemia. 2021 May;35(5):1405-1417. doi: 10.1038/s41375-021-01146-z. Epub 2021 Feb 4.
RGD ID: 155888491
Pubmed: PMID:33542482   (View Abstract at PubMed)
PMCID: PMC8102197   (View Article at PubMed Central)
DOI: DOI:10.1038/s41375-021-01146-z   (Journal Full-text)

Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A-Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A-Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
KMT2AHumanacute myeloid leukemia treatmentIMP human cell line in a mouse modelRGD 
Kmt2aMouseacute myeloid leukemia treatmentISOKMT2A (Homo sapiens)human cell line in a mouse modelRGD 
Kmt2aRatacute myeloid leukemia treatmentISOKMT2A (Homo sapiens)human cell line in a mouse modelRGD 

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