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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
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    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.
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