ArticleCell genomics2024
A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.
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Article in Cell genomics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 19 citations in OpenAlex.
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- Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.Science (New York, N.Y.) · 2026Article
- The Mutational Epidemiology of Childhood Cancer.Clinical chemistry · 2025Review
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- Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci.Nature communications · 2025Article
- Comprehensive Epigenome-Wide Profiling Reveals Distinctive DNA Methylation Signatures and Potential Prognostic Biomarkers in Mexican Pediatric B-ALL.International journal of molecular sciences · 2025Article
- Human genetic influences on early B cell development.Journal of human immunity · 2025Review
- Adult Acute Lymphoblastic Leukemia: 2025 Update on Diagnosis, Therapy, and Monitoring.American journal of hematology · 2025Review
- Altered Expression of NK Receptors in Racially/Ethnically Diverse and Risk-of-Relapse Pediatric Acute Lymphoblastic Leukemia Patients.Biomedicines · 2025Article
- Addressing Health Disparities in Hematologic Malignancies: from Genes to Outreach.Blood cancer discovery · 2025Review
- Evolution, genetic diversity, and health.Nature medicine · 2025Review
- Targeting hardship: poverty as a modifiable risk factor in childhood leukemia and lymphoma treatment.Hematology. American Society of Hematology. Education Program · 2024Review
- Ikaros Deletions among Bulgarian Patients with Acute Lymphoblastic Leukemia/Lymphoma.Diagnostics (Basel, Switzerland) · 2024Article
- Childhood B cell leukemia: Intercepting the paths to progression.BioEssays : news and reviews in molecular, cellular and developmental biology · 2024Review
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Authors and funding
25 authors at 9 institutions in 2 countries.
Adam J de SmithCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: desmith@usc.edu.
Lara WahlsterDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Soyoung JeonCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Linda KachuriDepartment of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA.
Susan BlackDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jalen LangieCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Liam D CatoDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nathan NakatsukaNew York Genome Center, New York, NY 10013, USA.
Tsz-Fung ChanCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Guangze XiaGMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
Soumyaa MazumderDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Wenjian YangDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Steven GazalCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Celeste EngDepartment of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Biotherapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Donglei HuDepartment of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Esteban González BurchardDepartment of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Biotherapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Elad ZivDepartment of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Catherine MetayerSchool of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
Nicholas MancusoCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Jun J YangDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Xiaomei MaYale School of Public Health, New Haven, CT 06520, USA.
Joseph L WiemelsCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Fulong YuDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
Charleston W K ChiangCenter for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Vijay G SankaranDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: sankaran@broadinstitute.org.
University of Southern California · USBroad Institute · USUniversity of California, San Francisco · USSt. Jude Children's Research Hospital · USGuangzhou Medical University · CNNew York Genome Center · USStanford University · USUniversity of California, Berkeley · USYale University · US
Funding
CALIFORNIA COORDINATED CANCER PREVENTION & CONTROL PROGRAMU58DP003862 · DP · CALIFORNIA STATE DEPT OF PUBLIC HEALTH · PI SNIPES, KURT P · 2012 to 2014
$31.5MNatural History of Viral Induced Airway Dysfunction and Asthma in Minority ChildrenU01HL138626 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI RODRIGUEZ-SANTANA, JOSE, SEIBOLD, MAX A · 2018 to 2022
$10.0MThe Airway Functional Genomics of Bronchodilator Drug Response in Minority Children with AsthmaR01HL117004 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, SEIBOLD, MAX A · 2013 to 2022
$9.3MRare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9MSystematic Genetic Dissection of Human ErythropoiesisR01DK103794 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2014 to 2026
$5.9MRare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6MGene-environments and Admixture in Latino Asthmatics (GALA 2)R01ES015794 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BURCHARD, ESTEBAN GONZALEZ · 2008 to 2012
$5.4MGenome-Wide Association Study of Childhood Leukemia by Hispanic StatusR01CA155461 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MA, XIAOMEI, WIEMELS, JOSEPH LEO · 2011 to 2014
$4.1MTranscriptomic and Pharmacogenetic Asthma Endotypes in Minority ChildrenR01HL135156 · NHLBI · NATIONAL JEWISH HEALTH · PI SEIBOLD, MAX A, ZIV, ELAD · 2017 to 2021
$4.1MUnderstanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in LatinosR01CA262263 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Adam De Smith · 2022 to 2026
$3.4MSelective pressures from inherited variation impacting myeloproliferative neoplasm initiationR01CA265726 · NCI · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2022 to 2026
$2.5MAn evolutionary framework to elucidate and interpret the genetic architecture of complex traits in diverse populations - diversity supplementR35GM142783 · NIGMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI CHIANG, CHARLESTON · 2021 to 2025
$2.2MNCCDPHP CDC HHS U58 DP003862NCI NIH HHS HHSN261201000034CNCI NIH HHS HHSN261201000035CNCI NIH HHS HHSN261201000035INCI NIH HHS HHSN261201000140CNCI NIH HHS R00 CA246076NCI NIH HHS R01 CA155461NCI NIH HHS R01 CA262263NCI NIH HHS R01 CA265726NCI NIH HHS R01 CA292941NHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS R01 HL117004NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL135156NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL138626NIA NIH HHS R01 AG033067NIDDK NIH HHS R01 DK103794NIEHS NIH HHS R01 ES015794NIGMS NIH HHS R35 GM142783
Abstract
Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.
Indexed as
Genetic Predisposition to DiseasePrecursor Cell Lymphoblastic Leukemia-LymphomaChildHispanic or LatinoHumansIkaros Transcription FactorPolymorphism, Single NucleotideTranscription FactorsIkaros Transcription FactorIKZF1 protein, humanTranscription Factorsacute lymphoblastic leukemiaB-ALLcancer disparitycancer predispositionchildhood leukemiafine-mappingGWAShematopoiesisIKZF1Indigenous American
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