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
Affiliations
- Matteo Marchesini
- Department of Medicine and Surgery, University of Parma
- Andrea Gherli
- Department of Medicine and Surgery, University of Parma
- Elisa Simoncini
- Department of Medicine and Surgery, University of Parma
- Lucas Moron Dalla Tor
- Department of Medicine and Surgery, University of Parma
- Anna Montanaro
- Department of Medicine and Surgery, University of Parma
- Natthakan Thongon
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Federica Vento
- Translational Hematology and Chemogenomics Laboratory, University of Parma
- Chiara Liverani
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
- Elisa Cerretani
- Translational Hematology and Chemogenomics Laboratory, University of Parma
- Anna D’Antuono
- Department of Medicine and Surgery, University of Parma
- Luca Pagliaro
- Department of Medicine and Surgery, University of Parma
- Raffaella Zamponi
- Department of Medicine and Surgery, University of Parma
- Chiara Spadazzi
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”
- Elena Follini
- Hematology and BMT Unit
- Benedetta Cambò
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma
- Mariateresa Giaimo
- Department of Medicine and Surgery, University of Parma
- Angela Falco
- Department of Medicine and Surgery, University of Parma
- Gabriella Sammarelli
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma
- Giannalisa Todaro
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma
- Sabrina Bonomini
- Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma
- Valentina Adami
- High-Throughput Screening Core Facility, CIBIO, University of Trento
- Silvano Piazza
- High-Throughput Screening Core Facility, CIBIO, University of Trento
- Claudia Corbo
- University of Milano-Bicocca, Department of Medicine and Surgery, NANOMIB Center
- Bruno Lorusso
- Department of Medicine and Surgery, University of Parma
- Federica Mezzasoma
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital
- Costanza Anna Maria Lagrasta
- Department of Medicine and Surgery, University of Parma
- Maria Paola Martelli
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital
- Roberta La Starza
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital
- Antonio Cuneo
- Department of Medical Science, University of Ferrara
- Franco Aversa
- Cristina Mecucci
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital
- Federico Quaini
- Department of Medicine and Surgery, University of Parma
- Simona Colla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center
- Giovanni Roti
- Department of Medicine and Surgery, University of Parma
- DOI
- https://doi.org/10.1038/s41467-024-48953-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
