2. Academic Validation
  3. Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML

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

  • Nat Commun. 2024 Jun 4;15(1):4739. doi: 10.1038/s41467-024-48953-3.
Matteo Marchesini 1 2 3,  Andrea Gherli # 1 2,  Elisa Simoncini # 1 2,  Lucas Moron Dalla Tor # 1 2,  Anna Montanaro 1 2,  Natthakan Thongon 4,  Federica Vento 2 5,  Chiara Liverani 3,  Elisa Cerretani 2 5,  Anna D'Antuono 1 2,  Luca Pagliaro 1 2 6,  Raffaella Zamponi 1 2,  Chiara Spadazzi 3,  Elena Follini 7,  Benedetta Cambò 6,  Mariateresa Giaimo 1 2 6,  Angela Falco 1,  Gabriella Sammarelli 6,  Giannalisa Todaro 6,  Sabrina Bonomini 6,  Valentina Adami 8,  Silvano Piazza 8 9,  Claudia Corbo 10 11,  Bruno Lorusso 1,  Federica Mezzasoma 12,  Costanza Anna Maria Lagrasta 1,  Maria Paola Martelli 12,  Roberta La Starza 12,  Antonio Cuneo 5 13,  Franco Aversa,  Cristina Mecucci 12,  Federico Quaini 1,  Simona Colla 4,  Giovanni Roti 14 15 16
Affiliations

Affiliations

  • 1 Department of Medicine and Surgery, University of Parma, Parma, Italy.
  • 2 Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.
  • 3 IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
  • 4 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Medical Science, University of Ferrara, Ferrara, Italy.
  • 6 Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
  • 7 Hematology and BMT Unit, Azienda USL Piacenza, Piacenza, Italy.
  • 8 High-Throughput Screening Core Facility, CIBIO, University of Trento, Trento, Italy.
  • 9 Computational Biology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
  • 10 University of Milano-Bicocca, Department of Medicine and Surgery, NANOMIB Center, Monza, Italy.
  • 11 IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
  • 12 Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital, Perugia, Italy.
  • 13 Hematology Unit, Azienda Ospedaliera-Universitaria S.ANNA, University of Ferrara, Ferrara, Italy.
  • 14 Department of Medicine and Surgery, University of Parma, Parma, Italy. giovanni.roti@unipr.it.
  • 15 Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy. giovanni.roti@unipr.it.
  • 16 Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. giovanni.roti@unipr.it.
  • # Contributed equally.
PMID: 38834613 DOI: 10.1038/s41467-024-48953-3
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.

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