Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci
B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P < 5 × 10<sup>-8</sup>) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10<sup>-3</sup>). Novel risk variants were also associated with subtype-specific disease (P < 0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower susceptibility for a subtype with excellent prognosis (ETV6-RUNX1). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity (P < 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.
Authors
- Luis Gil‐de‐Gómez (ORCID: https://orcid.org/0000-0002-7864-3976)
- Michael E. Scheurer (ORCID: https://orcid.org/0000-0002-8379-6088)
- Lucie M. Turcotte (ORCID: https://orcid.org/0000-0003-4106-6172)
- Lingyun Ji (ORCID: https://orcid.org/0000-0003-2500-1993)
- Laura J. Klesse (ORCID: https://orcid.org/0000-0003-1323-7720)
- Neerav Narendra Shukla (ORCID: https://orcid.org/0000-0003-2516-2965)
- Julie Wolfson (ORCID: https://orcid.org/0000-0002-3711-2239)
- Tianzhong Yang (ORCID: https://orcid.org/0000-0002-0162-7740)
- Robert J. Mobley (ORCID: https://orcid.org/0000-0002-2728-8206)
- Nathan Pankratz (ORCID: https://orcid.org/0000-0001-5958-693X)
- Danielle Novetsky Friedman (ORCID: https://orcid.org/0000-0003-4668-9176)
- Zhanni Lu (ORCID: https://orcid.org/0000-0001-9957-3527)
- Erin L. Marcotte (ORCID: https://orcid.org/0000-0002-9630-9701)
- Alix E. Seif (ORCID: https://orcid.org/0000-0002-1799-2582)
- Andrew Thomas DeWan (ORCID: https://orcid.org/0000-0002-7679-8704)
- Joseph Leo Wiemels (ORCID: https://orcid.org/0000-0003-4838-9951)
- Kelly R. Barnett (ORCID: https://orcid.org/0000-0001-9790-0352)
- Minjie Luo (ORCID: https://orcid.org/0000-0002-5788-3962)
- Matthew Tsang
- Adam J. de Smith (ORCID: https://orcid.org/0000-0003-4880-7543)
- Erica Langer (ORCID: https://orcid.org/0000-0002-4528-5922)
- Charleston W. K. Chiang (ORCID: https://orcid.org/0000-0002-0668-7865)
- Logan G. Spector (ORCID: https://orcid.org/0000-0003-2516-0222)
- Jun J. Yang (ORCID: https://orcid.org/0000-0002-0770-9659)
- Saonli Basu (ORCID: https://orcid.org/0000-0003-1200-4546)
- Lauren J. Mills (ORCID: https://orcid.org/0000-0002-8914-2587)
- Catherine Metayer (ORCID: https://orcid.org/0000-0003-3467-4145)
- Heather H. Nelson (ORCID: https://orcid.org/0000-0003-1901-9513)
- Alice Dang
- Kashi Raj Bhattarai (ORCID: https://orcid.org/0000-0003-4781-9067)
- Andrew R. Raduski (ORCID: https://orcid.org/0000-0002-7069-6934)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Yi-Ming Zhong (ORCID: https://orcid.org/0000-0001-9922-6162)
- Anthony J. Hooten
- Cindy Im (ORCID: https://orcid.org/0000-0003-0931-9432)
- Kenneth K. Liao (ORCID: https://orcid.org/0000-0002-2101-4925)
- Rebecca Johnson (ORCID: https://orcid.org/0000-0003-2475-6622)
- Daniel Savic (ORCID: https://orcid.org/0000-0002-6693-0265)
- Xiaomei Ma (ORCID: https://orcid.org/0000-0001-9472-8032)
- Jalen Langie (ORCID: https://orcid.org/0000-0002-9651-457X)
- Brandon Mamou
- Zhaoming Wang (ORCID: https://orcid.org/0000-0001-7556-3869)
- Nathan Anderson
Institutions
- University of Southern California (US)
- University of Minnesota (US)
- St. Jude Children's Research Hospital (US)
- Universidad de Cantabria (ES)
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Baylor College of Medicine (US)
- University of Alabama at Birmingham (US)
- Yale University (US)
- Children's Oncology Group (US)
- Texas Children's Hospital (US)
- The University of Texas Southwestern Medical Center (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1038/s41467-025-64337-7
- Citations
- 1
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 1.88
Funders
- Children's Cancer Research Fund
- California Department of Public Health
- University of Southern California
- University of Minnesota
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Cancer Institute