Nature Communications (Jun 2024)

Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML

  • Matteo Marchesini,
  • Andrea Gherli,
  • Elisa Simoncini,
  • Lucas Moron Dalla Tor,
  • Anna Montanaro,
  • Natthakan Thongon,
  • Federica Vento,
  • Chiara Liverani,
  • Elisa Cerretani,
  • Anna D’Antuono,
  • Luca Pagliaro,
  • Raffaella Zamponi,
  • Chiara Spadazzi,
  • Elena Follini,
  • Benedetta Cambò,
  • Mariateresa Giaimo,
  • Angela Falco,
  • Gabriella Sammarelli,
  • Giannalisa Todaro,
  • Sabrina Bonomini,
  • Valentina Adami,
  • Silvano Piazza,
  • Claudia Corbo,
  • Bruno Lorusso,
  • Federica Mezzasoma,
  • Costanza Anna Maria Lagrasta,
  • Maria Paola Martelli,
  • Roberta La Starza,
  • Antonio Cuneo,
  • Franco Aversa,
  • Cristina Mecucci,
  • Federico Quaini,
  • Simona Colla,
  • Giovanni Roti

DOI
https://doi.org/10.1038/s41467-024-48953-3
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 22

Abstract

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Abstract 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.