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A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros

Leukemia volume 30, pages 1194–1197 (2016)Cite this article

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Heritable single-nucleotide polymorphisms (SNPs) in six genomic loci have been associated with childhood acute lymphoblastic leukemia (ALL) risk in genome-wide association studies (GWAS) of European-ancestry populations. Four of these heritable ALL risk loci are near genes crucial for hematopoietic differentiation, including CEBPE.1, 2 CEBPE encodes one of a family of six known CCAAT-targeting bZIP transcription factors which critically regulate myelopoiesis. To identify causal polymorphisms underlying the childhood ALL association peak near CEBPE, we performed SNP genotyping, imputation-based fine-mapping, and functional validation analyses of the chromosome 14q11.2 locus in a multi-ethnic case–control population of Hispanic children from the California Childhood Leukemia Study (CCLS) and European-ancestry children from the Children’s Oncology Group, totaling 1277 cases and 3078 controls.

Supplementary Figure 1 and Supplementary Table 1 summarize the study design and study populations (full methods in online supplement). Briefly, 297 Hispanic B-cell ALL (B-ALL) cases and 454 Hispanic controls underwent genotyping and targeted fine-mapping. Additional GWAS data was used to perform imputation-based fine-mapping in 980 European-ancestry Children’s Oncology Group ALL subjects and 2624 Wellcome Trust Case Control Consortium controls.3 An additional 271 cases and 436 controls from the CCLS underwent targeted Sequenom genotyping. Association tests were performed using an allelic additive model, adjusted for ancestry-informative principal components.

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Acknowledgements

This work was financially supported by NCI R01CA155461 (JLW, KMW), NCI R25CA112355 (KMW), NIEHS and EPA P01ES018172 (CM, JLW), NIEHS R01ES09137 (CM, JLW), and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health P01DK088760 (MOM and MEF). A full list of acknowledgements can be found in the online supplement.

Author contributions

JLW and KMW designed experiments, analyzed the data, and wrote the manuscript. AJdS and JQ designed and performed experiments and helped write the manuscript. S-TL helped analyze the data. MOM and MEF supplied key reagents and helped perform experiments. MZ and HH performed experiments. AT and CM secured clinical and population samples. All authors read and finalized the manuscript.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    J L Wiemels, A J de Smith, J Xiao & M Zhou

  2. Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

    J L Wiemels, H M Hansen & K M Walsh

  3. Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    S-T Lee & M O Muench

  4. Blood Systems Research Institute and Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

    M E Fomin

  5. Department of Pediatrics, Jonathan Jaques Children's Cancer Center, Keck School of Medicine, University of South California, Long Beach, CA, USA

    A Termuhlen

  6. School of Public Health, University of California Berkeley, Berkeley, CA, USA

    C Metayer

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  1. J L Wiemels
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Correspondence to J L Wiemels.

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Wiemels, J., de Smith, A., Xiao, J. et al. A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros. Leukemia 30, 1194–1197 (2016). https://doi.org/10.1038/leu.2015.251

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