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. 2025 Sep 1;6(5):412-424.
doi: 10.1158/2643-3230.BCD-25-0049. Epub 2025 May 28.

Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia

Haley Newman  1 , Shawn H R Lee  2 , Petri Pölönen  3 , Rawan Shraim  1 , Yimei Li  4 , Hongyan Liu  4 , Richard Aplenc  1 , Shovik Bandyopadhyay  5 , Changya Chen  4 , Meenakshi Devidas  6 , Caroline Diorio  1 , Kimberly Dunsmore  7 , Omar Elghawy  5 , Amira Elhachimi  4 , Tori Fuller  4 , Sumit Gupta  8 , Junior Hall  4 , Andrew D Hughes  4 , Stephen P Hunger  1 , Mignon L Loh  9 , Zachary Martinez  4 , Michael F McCoy  10 , Cassidy G Mullen  4 , Stanley B Pounds  11 , Elizabeth Raetz  12 , Anna Eames Seffernick  6 , Gongping Shi  1 , Jonathan Sussman  5 , Kai Tan  1 , Lahari Uppuluri  4 , Tiffaney L Vincent  10 , Ruth Wang'ondu  6 , Lena E Winestone  13 , Stuart S Winter  14 , Brent L Wood  15 , Gang Wu  3 , Jason Xu  16 , Wenjian Yang  11 , Charles G Mullighan  3 , Jun J Yang  3 , Kira Bona  17 , David T Teachey  1
Affiliations

Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia

Haley Newman et al. Blood Cancer Discov. .

Abstract

The influence of genetic ancestry on genomics in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been fully explored. We examined the impact of genetic ancestry on multi-omic alterations, survival outcomes, and risk stratification. Among 1309 children and young adults with T-ALL treated on the Children's Oncology Group trial AALL0434, the prognostic value of five commonly altered T-ALL genes varied by ancestry-including NOTCH1, which was associated with superior overall survival for patients of European ancestry but non-prognostic among patients of African ancestry. Integrating genetic ancestry with published T-ALL risk classifiers, we identified that a X01 Penalized Cox Regression classifier stratified patients regardless of ancestry, whereas a European multi-gene classifier misclassified patients of certain ancestries. Overall, 80% of patients harbored a genomic alteration in at least one gene with differential prognostic impact in an ancestry-specific manner. These data demonstrate the importance of incorporating genetic ancestry into genomic risk classification.

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Conflict of interest statement

S. Bandyopadhyay reports grants from the NIH during the conduct of the study. C. Diorio reports personal fees from Merck outside the submitted work. S.P. Hunger reports other support from Amgen, Jazz Pharmaceuticals, and Servier outside the submitted work. M.L. Loh reports personal fees from Jazz Pharmaceuticals outside the submitted work. S.B. Pounds reports grants from the NIH during the conduct of the study. E. Raetz reports other support from Bristol Myers Squibb and grants from Pfizer outside the submitted work. A.E. Seffernick reports other support from Eli Lilly and Company outside the submitted work; employment with Lilly and ownership of Lilly stock; and that this work was completed prior to her employment at Lilly, she is acting entirely on her own, and these endeavors are not in any manner affiliated with Lilly. B.L. Wood reports grants from the COG during the conduct of the study as well as personal fees from Amgen outside the submitted work. C.G. Mullighan reports personal fees from Illumina during the conduct of the study as well as grants from Pfizer and AbbVie and personal fees from Amgen outside the submitted work and that he has a patent for Cyrus with royalties paid. J.J. Yang reports grants from Takeda Pharmaceutical Company and AstraZeneca outside the submitted work. D.T. Teachey reports grants from the NIH, Hyundai Hope on Wheels, Alex’s Lemonade Stand Foundation, Pennsylvania Department of Health, St. Baldrick’s Foundation, Harris Willing Memorial Research Fund, The Invisible Prince Foundation, and the Aiden Everett Davies Innovation Fund during the conduct of the study as well as nonfinancial support from Amgen, Johnson & Johnson Innovation, Sobi, Servier, Jazz Pharmaceuticals, Novartis, and Pfizer; grants and nonfinancial support from BEAM Therapeutics; and grants from NeoImmuneTech outside the submitted work. No disclosures were reported by the other authors.

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