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Menin is necessary for long term maintenance of meningioma-1 driven leukemia
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Journal Article
Menin is necessary for long term maintenance of meningioma-1 driven leukemia
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/100
/ 13/106
/ 13/31
/ 14/63
/ 38/39
/ 42/44
/ 64/60
/ 96/2
/ 96/21
/ Animals
/ Gene Expression Regulation, Leukemic - genetics
/ Histone-Lysine N-Methyltransferase - genetics
/ Humans
/ Kinases
/ Leukemia
/ Leukemia, Myeloid, Acute - genetics
/ Medicine
/ Mice
/ Oncology
/ Proteins
/ Proto-Oncogene Proteins - genetics
