Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia
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 tw...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56229-7 |
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| author | 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 Jun J. Yang |
| author_facet | 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 Jun J. Yang |
| author_sort | Zhenhua Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-562e9f63581748ccad0f23b2bea2b748 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-562e9f63581748ccad0f23b2bea2b7482025-02-02T12:32:20ZengNature PortfolioNature Communications2041-17232025-01-0116111110.1038/s41467-025-56229-7Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemiaZhenhua Li0Huanbin Zhao1Wenjian Yang2Maud Maillard3Satoshi Yoshimura4Yu-Chih Hsiao5Xin Huang6Yoshihiro Gocho7Lauren Rowland8Anthony Brown9Landon Choi10Kristine R. Crews11Charles G. Mullighan12Samuel W. Brady13Cheng Cheng14Ti-Cheng Chang15Gang Wu16Mignon L. Loh17Allen Eng Juh Yeoh18Federico Antillon-Klussmann19Sima Jeha20Hiroto Inaba21Jiyang Yu22Ching-Hon Pui23Seth E. Karol24William E. Evans25Jun J. Yang26Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Biostatistics, St. Jude Children’s Research HospitalCenter for Applied Bioinformatics, St Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of WashingtonKhoo Teck Puat – National University Children’s Medical Institute, National University Hospital, National University Health SystemNational Pediatric Oncology UnitDepartment of Oncology, St. Jude Children’s Research HospitalDepartment of Oncology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Oncology, St. Jude Children’s Research HospitalDepartment of Oncology, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research HospitalAbstract 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.https://doi.org/10.1038/s41467-025-56229-7 |
| spellingShingle | 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 Jun J. Yang Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia Nature Communications |
| title | Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia |
| title_full | Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia |
| title_fullStr | Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia |
| title_full_unstemmed | Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia |
| title_short | Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia |
| title_sort | molecular and pharmacological heterogeneity of etv6 runx1 acute lymphoblastic leukemia |
| url | https://doi.org/10.1038/s41467-025-56229-7 |
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