A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children

Adam J de Smith; Lara Wahlster; Soyoung Jeon; Linda Kachuri; Susan Black; Jalen Langie; Liam D Cato; Nathan Nakatsuka; Tsz-Fung Chan; Guangze Xia; Soumyaa Mazumder; Wenjian Yang; Steven Gazal; Celeste Eng; Donglei Hu; Esteban González Burchard; Elad Ziv; Catherine Metayer; Nicholas Mancuso; Jun J Yang; Xiaomei Ma; Joseph L Wiemels; Fulong Yu; Charleston W K Chiang; Vijay G Sankaran

doi:10.1016/j.xgen.2024.100526

A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children

Cell Genom. 2024 Apr 10;4(4):100526. doi: 10.1016/j.xgen.2024.100526. Epub 2024 Mar 26.

Authors

Adam J de Smith¹, Lara Wahlster², Soyoung Jeon³, Linda Kachuri⁴, Susan Black², Jalen Langie³, Liam D Cato², Nathan Nakatsuka⁵, Tsz-Fung Chan³, Guangze Xia⁶, Soumyaa Mazumder², Wenjian Yang⁷, Steven Gazal³, Celeste Eng⁸, Donglei Hu⁹, Esteban González Burchard⁸, Elad Ziv⁹, Catherine Metayer¹⁰, Nicholas Mancuso³, Jun J Yang⁷, Xiaomei Ma¹¹, Joseph L Wiemels³, Fulong Yu¹², Charleston W K Chiang³, Vijay G Sankaran¹³

Affiliations

¹ Center 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.
² Division 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.
³ Center 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.
⁴ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ New York Genome Center, New York, NY 10013, USA.
⁶ 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.
⁷ Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁸ Department 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.
⁹ Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
¹¹ Yale School of Public Health, New Haven, CT 06520, USA.
¹² Division 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.
¹³ Division 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.

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.

Keywords: B-ALL; GWAS; IKZF1; Indigenous American; acute lymphoblastic leukemia; cancer disparity; cancer predisposition; childhood leukemia; fine-mapping; hematopoiesis.

MeSH terms

Child
Genetic Predisposition to Disease* / genetics
Hispanic or Latino / genetics
Humans
Ikaros Transcription Factor / genetics
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
Transcription Factors / genetics

Substances

Transcription Factors
IKZF1 protein, human
Ikaros Transcription Factor

Abstract

MeSH terms

Substances

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