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

Author

Listed:
  • Matteo Marchesini

    (University of Parma
    University of Parma
    IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”)

  • Andrea Gherli

    (University of Parma
    University of Parma)

  • Elisa Simoncini

    (University of Parma
    University of Parma)

  • Lucas Moron Dalla Tor

    (University of Parma
    University of Parma)

  • Anna Montanaro

    (University of Parma
    University of Parma)

  • Natthakan Thongon

    (The University of Texas MD Anderson Cancer Center)

  • Federica Vento

    (University of Parma
    University of Ferrara)

  • Chiara Liverani

    (IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”)

  • Elisa Cerretani

    (University of Parma
    University of Ferrara)

  • Anna D’Antuono

    (University of Parma
    University of Parma)

  • Luca Pagliaro

    (University of Parma
    University of Parma
    Azienda Ospedaliero-Universitaria di Parma)

  • Raffaella Zamponi

    (University of Parma
    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
    University of Parma
    Azienda Ospedaliero-Universitaria di 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
    International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Claudia Corbo

    (NANOMIB Center
    IRCCS Istituto Ortopedico Galeazzi)

  • 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
    University of Ferrara)

  • Franco Aversa
  • 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
    University of Parma
    Azienda Ospedaliero-Universitaria di Parma)

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.

Suggested Citation

  • 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 &, 2024. "Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48953-3
    DOI: 10.1038/s41467-024-48953-3
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    References listed on IDEAS

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    1. Marcin Pilarczyk & Mehdi Fazel-Najafabadi & Michal Kouril & Behrouz Shamsaei & Juozas Vasiliauskas & Wen Niu & Naim Mahi & Lixia Zhang & Nicholas A. Clark & Yan Ren & Shana White & Rashid Karim & Huan, 2022. "Connecting omics signatures and revealing biological mechanisms with iLINCS," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. David A. Barbie & Pablo Tamayo & Jesse S. Boehm & So Young Kim & Susan E. Moody & Ian F. Dunn & Anna C. Schinzel & Peter Sandy & Etienne Meylan & Claudia Scholl & Stefan Fröhling & Edmond M. Chan & Ma, 2009. "Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1," Nature, Nature, vol. 462(7269), pages 108-112, November.
    3. Jeffrey W. Tyner & Cristina E. Tognon & Daniel Bottomly & Beth Wilmot & Stephen E. Kurtz & Samantha L. Savage & Nicola Long & Anna Reister Schultz & Elie Traer & Melissa Abel & Anupriya Agarwal & Auro, 2018. "Functional genomic landscape of acute myeloid leukaemia," Nature, Nature, vol. 562(7728), pages 526-531, October.
    4. Sophie Ottema & Roger Mulet-Lazaro & Claudia Erpelinck-Verschueren & Stanley van Herk & Marije Havermans & Andrea Arricibita Varea & Michael Vermeulen & H. Berna Beverloo & Stefan Gröschel & Torsten H, 2021. "The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Lianjun Zhang & Le Xuan Truong Nguyen & Ying-Chieh Chen & Dijiong Wu & Guerry J. Cook & Dinh Hoa Hoang & Casey J. Brewer & Xin He & Haojie Dong & Shu Li & Man Li & Dandan Zhao & Jing Qi & Wei-Kai Hua , 2021. "Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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