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Updated: Jun 24, 2025

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML

Matteo Marchesini1,2,3, Andrea Gherli1,2, Elisa Simoncini1,2

  • 1Department of Medicine and Surgery, University of Parma, Parma, Italy.

Nature Communications
|June 4, 2024
PubMed

Insights

Histone deacetylase inhibitors (HDACis) repress the EVI1 gene in acute myeloid leukemia (AML). Targeting the PA2G4 protein enhances HDACi efficacy, offering new therapeutic strategies for 3q26 AML.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Ecotropic viral integration site-1 (EVI1/MECOM) gene overexpression defines a lethal subgroup of acute myeloid leukemia (AML) with 3q26 abnormalities.
  • Histone deacetylase inhibitors (HDACis) show potential for repressing EVI1, but their precise mechanism in 3q26 AML requires elucidation.

Purpose of the Study:

  • To investigate the anti-leukemia mechanism of HDACis in 3q26 AML by dissecting EVI1 regulation.
  • To identify key proteins interacting with EVI1 in the co-transcriptional complex and their role in HDACi response.

Main Methods:

  • High-throughput cell-based and gene expression screening to identify EVI1 repressors.
  • Analysis of bone marrow leukemia cell expression dynamics in patients treated with HDAC inhibitors.
  • Reconstitution of the EVI1 chromatin-associated co-transcriptional complex, focusing on the proliferation-associated 2G4 (PA2G4) protein.

Main Results:

  • PA2G4 overexpression confers resistance to HDACis in AML cells.
  • Genetic and small molecule inhibition of PA2G4 effectively abrogates EVI1 expression in 3q26 AML cells and patient-derived xenografts.
  • PA2G4 plays a critical role in mediating the EVI1 leukemogenic signal.

Conclusions:

  • PA2G4 is a crucial mediator of the EVI1 oncogenic pathway in 3q26 AML.
  • Targeting PA2G4 in combination with HDACis presents a promising therapeutic strategy for 3q26 AML.
  • This research highlights PA2G4 as a potential therapeutic target for developing novel treatments for this aggressive AML subtype.

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