IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56229-7.html
   My bibliography  Save this article

Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia

Author

Listed:
  • Zhenhua Li

    (St. Jude Children’s Research Hospital)

  • Huanbin Zhao

    (St. Jude Children’s Research Hospital)

  • Wenjian Yang

    (St. Jude Children’s Research Hospital)

  • Maud Maillard

    (St. Jude Children’s Research Hospital)

  • Satoshi Yoshimura

    (St. Jude Children’s Research Hospital)

  • Yu-Chih Hsiao

    (St. Jude Children’s Research Hospital)

  • Xin Huang

    (St. Jude Children’s Research Hospital)

  • Yoshihiro Gocho

    (St. Jude Children’s Research Hospital)

  • Lauren Rowland

    (St. Jude Children’s Research Hospital)

  • Anthony Brown

    (St. Jude Children’s Research Hospital)

  • Landon Choi

    (St. Jude Children’s Research Hospital)

  • Kristine R. Crews

    (St. Jude Children’s Research Hospital)

  • Charles G. Mullighan

    (St. Jude Children’s Research Hospital)

  • Samuel W. Brady

    (St. Jude Children’s Research Hospital)

  • Cheng Cheng

    (St. Jude Children’s Research Hospital)

  • Ti-Cheng Chang

    (St Jude Children’s Research Hospital)

  • Gang Wu

    (St. Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

  • Mignon L. Loh

    (University of Washington)

  • Allen Eng Juh Yeoh

    (National University Health System
    National University of Singapore)

  • Federico Antillon-Klussmann

    (National Pediatric Oncology Unit
    Francisco Marroquin University)

  • Sima Jeha

    (St. Jude Children’s Research Hospital)

  • Hiroto Inaba

    (St. Jude Children’s Research Hospital)

  • Jiyang Yu

    (St. Jude Children’s Research Hospital)

  • Ching-Hon Pui

    (St. Jude Children’s Research Hospital)

  • Seth E. Karol

    (St. Jude Children’s Research Hospital)

  • William E. Evans

    (St. Jude Children’s Research Hospital)

  • Jun J. Yang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

Abstract

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL) associated with favorable prognosis, but the optimal therapy for this subtype remains unclear. Profiling the genomic and pharmacological landscape of 194 pediatric ETV6::RUNX1 ALL cases, we uncover two transcriptomic clusters, C1 (61%) and C2 (39%). Compared to C1, the C2 subtype features higher white blood cell counts and younger age at diagnosis, as well as better early treatment responses. Pharmacologically, C2 is more sensitive to thiopurines and prednisolone, partially explained by the enrichment of PAX5 deletions. Re-introducing PAX5 in ETV6::RUNX1 ALL of the C2 subtype converts its gene expression and drug resistance profile to C1, with partial blockade of G1 to S transition mediated by CDK6 expression. Our results point to molecular heterogeneity within ETV6::RUNX1 ALL linked to divergent drug responses, providing insights into the pathogenesis and therapeutic vulnerability of this common pediatric ALL subtype.

Suggested Citation

  • Zhenhua Li & Huanbin Zhao & Wenjian Yang & Maud Maillard & Satoshi Yoshimura & Yu-Chih Hsiao & Xin Huang & Yoshihiro Gocho & Lauren Rowland & Anthony Brown & Landon Choi & Kristine R. Crews & Charles , 2025. "Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56229-7
    DOI: 10.1038/s41467-025-56229-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56229-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56229-7?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. Kristina Anderson & Christoph Lutz & Frederik W. van Delft & Caroline M. Bateman & Yanping Guo & Susan M. Colman & Helena Kempski & Anthony V. Moorman & Ian Titley & John Swansbury & Lyndal Kearney & , 2011. "Genetic variegation of clonal architecture and propagating cells in leukaemia," Nature, Nature, vol. 469(7330), pages 356-361, January.
    2. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    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. Yasuhiko Haga & Yoshitaka Sakamoto & Keiko Kajiya & Hitomi Kawai & Miho Oka & Noriko Motoi & Masayuki Shirasawa & Masaya Yotsukura & Shun-Ichi Watanabe & Miyuki Arai & Junko Zenkoh & Kouya Shiraishi &, 2023. "Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Jonathan C. M. Wan & Dennis Stephens & Lingqi Luo & James R. White & Caitlin M. Stewart & Benoît Rousseau & Dana W. Y. Tsui & Luis A. Diaz, 2022. "Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Yi-Ing Chen & Chin-Chun Chang & Min-Fen Hsu & Yung-Ming Jeng & Yu-Wen Tien & Ming-Chu Chang & Yu-Ting Chang & Chun-Mei Hu & Wen-Hwa Lee, 2022. "Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Teresa Maria Rosaria Noviello & Anna Maria Giacomo & Francesca Pia Caruso & Alessia Covre & Roberta Mortarini & Giovanni Scala & Maria Claudia Costa & Sandra Coral & Wolf H. Fridman & Catherine Sautès, 2023. "Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Thomas R. W. Oliver & Lia Chappell & Rashesh Sanghvi & Lauren Deighton & Naser Ansari-Pour & Stefan C. Dentro & Matthew D. Young & Tim H. H. Coorens & Hyunchul Jung & Tim Butler & Matthew D. C. Nevill, 2022. "Clonal diversification and histogenesis of malignant germ cell tumours," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Rotem Katzir & Noam Rudberg & Keren Yizhak, 2022. "Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Ewart Kuijk & Onno Kranenburg & Edwin Cuppen & Arne Van Hoeck, 2022. "Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    10. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    11. Sophie Pénisson & Amaury Lambert & Cristian Tomasetti, 2022. "Evaluating cancer etiology and risk with a mathematical model of tumor evolution," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    12. Sujath Abbas & Oriol Pich & Ginny Devonshire & Shahriar A. Zamani & Annalise Katz-Summercorn & Sarah Killcoyne & Calvin Cheah & Barbara Nutzinger & Nicola Grehan & Nuria Lopez-Bigas & Rebecca C. Fitzg, 2023. "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Chengdi Wang & Jingwei Li & Jingyao Chen & Zhoufeng Wang & Guonian Zhu & Lujia Song & Jiayang Wu & Changshu Li & Rong Qiu & Xuelan Chen & Li Zhang & Weimin Li, 2025. "Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    14. Noah Sasa & Toshihiro Kishikawa & Masashi Mori & Rie Ito & Yumie Mizoro & Masami Suzuki & Hirotaka Eguchi & Hidenori Tanaka & Takahito Fukusumi & Motoyuki Suzuki & Yukinori Takenaka & Keisuke Nimura &, 2025. "Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    15. Pierre Murat & Guillaume Guilbaud & Julian E. Sale, 2024. "DNA replication initiation drives focal mutagenesis and rearrangements in human cancers," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Sriram Vijayraghavan & Thomas Blouin & James McCollum & Latarsha Porcher & François Virard & Jiri Zavadil & Carol Feghali-Bostwick & Natalie Saini, 2024. "Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    17. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    18. Eline J. M. Bertrums & Jurrian K. Kanter & Lucca L. M. Derks & Mark Verheul & Laurianne Trabut & Markus J. Roosmalen & Henrik Hasle & Evangelia Antoniou & Dirk Reinhardt & Michael N. Dworzak & Nora Mü, 2024. "Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Mariarosaria Rosa & Ryan P. Barnes & Ariana C. Detwiler & Prasanth R. Nyalapatla & Peter Wipf & Patricia L. Opresko, 2025. "OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    20. Jonathan E. Shoag & Amoolya Srinivasa & Caitlin A. Loh & Mei Hong Liu & Emilie Lassen & Shana Melanaphy & Benjamin M. Costa & Marta Grońska-Pęski & Nisrine T. Jabara & Shany Picciotto & Una Choi & Any, 2025. "Direct measurement of the male germline mutation rate in individuals using sequential sperm samples," Nature Communications, Nature, vol. 16(1), pages 1-13, 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:16:y:2025:i:1:d:10.1038_s41467-025-56229-7. 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.