IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48953-3.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48953-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-48953-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Roger Mulet-Lazaro & Stanley Herk & Margit Nuetzel & Aniko Sijs-Szabo & Noelia Díaz & Katherine Kelly & Claudia Erpelinck-Verschueren & Lucia Schwarzfischer-Pfeilschifter & Hanna Stanewsky & Ute Acker, 2024. "Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Elizabeth Heyes & Anna S. Wilhelmson & Anne Wenzel & Gabriele Manhart & Thomas Eder & Mikkel B. Schuster & Edwin Rzepa & Sachin Pundhir & Teresa D’Altri & Anne-Katrine Frank & Coline Gentil & Jakob Wo, 2023. "TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Qingnan Liang & Yuefan Huang & Shan He & Ken Chen, 2023. "Pathway centric analysis for single-cell RNA-seq and spatial transcriptomics data with GSDensity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. J. McClatchy & R. Strogantsev & E. Wolfe & H. Y. Lin & M. Mohammadhosseini & B. A. Davis & C. Eden & D. Goldman & W. H. Fleming & P. Conley & G. Wu & L. Cimmino & H. Mohammed & A. Agarwal, 2023. "Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Yue Wang & Dhamotharan Pattarayan & Haozhe Huang & Yueshan Zhao & Sihan Li & Yifei Wang & Min Zhang & Song Li & Da Yang, 2024. "Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Yan Li & Chen Xu & Bing Wang & Fujiang Xu & Fahan Ma & Yuanyuan Qu & Dongxian Jiang & Kai Li & Jinwen Feng & Sha Tian & Xiaohui Wu & Yunzhi Wang & Yang Liu & Zhaoyu Qin & Yalan Liu & Jing Qin & Qi Son, 2022. "Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    8. Rebecca Anderson & Lance D. Miller & Scott Isom & Jeff W. Chou & Kristin M. Pladna & Nathaniel J. Schramm & Leslie R. Ellis & Dianna S. Howard & Rupali R. Bhave & Megan Manuel & Sarah Dralle & Susan L, 2022. "Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Fei Wu & Huixun Du & Eliah Overbey & JangKeun Kim & Priya Makhijani & Nicolas Martin & Chad A. Lerner & Khiem Nguyen & Jordan Baechle & Taylor R. Valentino & Matias Fuentealba & Juliet M. Bartleson & , 2024. "Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    10. Augusto Faria Andrade & Alva Annett & Elham Karimi & Danai Georgia Topouza & Morteza Rezanejad & Yitong Liu & Michael McNicholas & Eduardo G. Gonzalez Santiago & Dhana Llivichuzhca-Loja & Arne Gehlhaa, 2024. "Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Davide Bernareggi & Qi Xie & Briana C. Prager & Jiyoung Yun & Luisjesus S. Cruz & Timothy V. Pham & William Kim & Xiqing Lee & Michael Coffey & Cristina Zalfa & Pardis Azmoon & Huang Zhu & Pablo Tamay, 2022. "CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    12. Hanlin Wang & Guanghao Luo & Xiaobei Hu & Gaoya Xu & Tao Wang & Minmin Liu & Xiaohui Qiu & Jianan Li & Jingfeng Fu & Bo Feng & Yutong Tu & Weijuan Kan & Chang Wang & Ran Xu & Yubo Zhou & Jianmin Yang , 2023. "Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Jenniffer Linares & Anna Sallent-Aragay & Jordi Badia-Ramentol & Alba Recort-Bascuas & Ana Méndez & Noemí Manero-Rupérez & Daniele Lo Re & Elisa I. Rivas & Marc Guiu & Melissa Zwick & Mar Iglesias & C, 2023. "Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Bofei Wang & Patrick K. Reville & Mhd Yousuf Yassouf & Fatima Z. Jelloul & Christopher Ly & Poonam N. Desai & Zhe Wang & Pamella Borges & Ivo Veletic & Enes Dasdemir & Jared K. Burks & Guilin Tang & S, 2024. "Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    15. David Wang & Mathieu Quesnel-Vallieres & San Jewell & Moein Elzubeir & Kristen Lynch & Andrei Thomas-Tikhonenko & Yoseph Barash, 2023. "A Bayesian model for unsupervised detection of RNA splicing based subtypes in cancers," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    17. Kang Wang & Ioannis Zerdes & Henrik J. Johansson & Dhifaf Sarhan & Yizhe Sun & Dimitris C. Kanellis & Emmanouil G. Sifakis & Artur Mezheyeuski & Xingrong Liu & Niklas Loman & Ingrid Hedenfalk & Jonas , 2024. "Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    18. Brian D. Lehmann & Antonio Colaprico & Tiago C. Silva & Jianjiao Chen & Hanbing An & Yuguang Ban & Hanchen Huang & Lily Wang & Jamaal L. James & Justin M. Balko & Paula I. Gonzalez-Ericsson & Melinda , 2021. "Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    19. Eduardo Gomez-Bañuelos & Yikai Yu & Jessica Li & Kevin S. Cashman & Merlin Paz & Maria Isabel Trejo-Zambrano & Regina Bugrovsky & Youliang Wang & Asiya Seema Chida & Cheryl A. Sherman-Baust & Dylan P., 2023. "Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    20. Qilin Zhang & Ziyan Xu & Rui Han & Yunzhi Wang & Zhen Ye & Jiajun Zhu & Yixin Cai & Fan Zhang & Jiangyan Zhao & Boyuan Yao & Zhaoyu Qin & Nidan Qiao & Ruofan Huang & Jinwen Feng & Yongfei Wang & Wenti, 2024. "Proteogenomic characterization of skull-base chordoma," Nature Communications, Nature, vol. 15(1), pages 1-32, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48953-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.