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 Starza, Antonio Cuneo, Franco Aversa, Cristina Mecucci, Federico Quaini, Simona Colla and Giovanni Roti ()
Additional contact information
Matteo Marchesini: University of Parma
Andrea Gherli: University of Parma
Elisa Simoncini: University of Parma
Lucas Moron Dalla Tor: University of Parma
Anna Montanaro: University of Parma
Natthakan Thongon: The University of Texas MD Anderson Cancer Center
Federica Vento: University of Parma
Chiara Liverani: IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
Elisa Cerretani: University of Parma
Anna D’Antuono: University of Parma
Luca Pagliaro: University of Parma
Raffaella Zamponi: University of Parma
Chiara Spadazzi: IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
Elena Follini: Hematology and BMT Unit
Benedetta Cambò: Azienda Ospedaliero-Universitaria di Parma
Mariateresa Giaimo: University of Parma
Angela Falco: University of Parma
Gabriella Sammarelli: Azienda Ospedaliero-Universitaria di Parma
Giannalisa Todaro: Azienda Ospedaliero-Universitaria di Parma
Sabrina Bonomini: Azienda Ospedaliero-Universitaria di Parma
Valentina Adami: University of Trento
Silvano Piazza: University of Trento
Claudia Corbo: NANOMIB Center
Bruno Lorusso: University of Parma
Federica Mezzasoma: University of Perugia and Santa Maria Della Misericordia Hospital
Costanza Anna Maria Lagrasta: University of Parma
Maria Paola Martelli: University of Perugia and Santa Maria Della Misericordia Hospital
Roberta Starza: University of Perugia and Santa Maria Della Misericordia Hospital
Antonio Cuneo: University of Ferrara
Cristina Mecucci: University of Perugia and Santa Maria Della Misericordia Hospital
Federico Quaini: University of Parma
Simona Colla: The University of Texas MD Anderson Cancer Center
Giovanni Roti: University of Parma

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48953-3

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