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

Autor: Marchesini M; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Gherli A; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Simoncini E; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Tor LMD; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Montanaro A; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Thongon N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Vento F; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.; Department of Medical Science, University of Ferrara, Ferrara, Italy., Liverani C; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Cerretani E; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.; Department of Medical Science, University of Ferrara, Ferrara, Italy., D'Antuono A; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Pagliaro L; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Zamponi R; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy., Spadazzi C; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy., Follini E; Hematology and BMT Unit, Azienda USL Piacenza, Piacenza, Italy., Cambò B; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Giaimo M; Department of Medicine and Surgery, University of Parma, Parma, Italy.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy.; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Falco A; Department of Medicine and Surgery, University of Parma, Parma, Italy., Sammarelli G; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Todaro G; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Bonomini S; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy., Adami V; High-Throughput Screening Core Facility, CIBIO, University of Trento, Trento, Italy., Piazza S; High-Throughput Screening Core Facility, CIBIO, University of Trento, Trento, Italy.; Computational Biology group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Corbo C; University of Milano-Bicocca, Department of Medicine and Surgery, NANOMIB Center, Monza, Italy.; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy., Lorusso B; Department of Medicine and Surgery, University of Parma, Parma, Italy., Mezzasoma F; Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital, Perugia, Italy., Lagrasta CAM; Department of Medicine and Surgery, University of Parma, Parma, Italy., Martelli MP; Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital, Perugia, Italy., La Starza R; Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital, Perugia, Italy., Cuneo A; Department of Medical Science, University of Ferrara, Ferrara, Italy.; Hematology Unit, Azienda Ospedaliera-Universitaria S.ANNA, University of Ferrara, Ferrara, Italy., Aversa F, Mecucci C; Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria Della Misericordia Hospital, Perugia, Italy., Quaini F; Department of Medicine and Surgery, University of Parma, Parma, Italy., Colla S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Roti G; Department of Medicine and Surgery, University of Parma, Parma, Italy. giovanni.roti@unipr.it.; Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, Italy. giovanni.roti@unipr.it.; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. giovanni.roti@unipr.it.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 04; Vol. 15 (1), pp. 4739. Date of Electronic Publication: 2024 Jun 04.
DOI: 10.1038/s41467-024-48953-3
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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