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Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
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Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
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Journal Article
Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
2024
Overview
The overexpression of the ecotropic viral integration site-1 gene (
EVI1/MECOM
) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of
EVI1
. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the
EVI1
chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein.
PA2G4
overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.
The overexpression of the ecotropic viral integration site-1 gene (
EVI1/MECOM
) marks the most lethal acute myeloid leukemia subgroup carrying 3q26 abnormalities. Here, pan-histone deacetylase inhibitors are identified as potent repressors of EVI1 and PA2G4 as a druggable target.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Animals
/ Cell Proliferation - drug effects
/ Cell Proliferation - genetics
/ Chromosomes, Human, Pair 3 - genetics
/ Female
/ Gene Expression Regulation, Leukemic - drug effects
/ Histone Deacetylase Inhibitors - pharmacology
/ Histones
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Leukemia, Myeloid, Acute - drug therapy
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - metabolism
/ Leukemia, Myeloid, Acute - pathology
/ MDS1 and EVI1 Complex Locus Protein - genetics
/ MDS1 and EVI1 Complex Locus Protein - metabolism
/ Mice
/ Proto-Oncogene Proteins c-myc - genetics
/ Proto-Oncogene Proteins c-myc - metabolism
/ Science
