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

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 G. Mullighan, Samuel W. Brady, Cheng Cheng, Ti-Cheng Chang, Gang Wu, Mignon L. Loh, Allen Eng Juh Yeoh, Federico Antillon-Klussmann, Sima Jeha, Hiroto Inaba, Jiyang Yu, Ching-Hon Pui, Seth E. Karol, William E. Evans and Jun J. Yang ()
Additional contact information
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
Mignon L. Loh: University of Washington
Allen Eng Juh Yeoh: National University Health System
Federico Antillon-Klussmann: National Pediatric Oncology Unit
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

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56229-7

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