1. Enhancer polymorphisms at the IKZF1 susceptibility locus for acute lymphoblastic leukemia impact B-cell proliferation and differentiation in both Down syndrome and non-Down syndrome genetic backgrounds.
- Author
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Gant VU, Junco JJ, Terrell M, Rashid R, and Rabin KR
- Subjects
- Alleles, Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Differentiation genetics, Cell Line, Tumor, Cell Proliferation genetics, DNA-Binding Proteins genetics, Down Syndrome complications, Down Syndrome genetics, Down Syndrome metabolism, Gene Frequency genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Genotype, HEK293 Cells, Hematopoietic Stem Cells metabolism, Homozygote, Humans, Ikaros Transcription Factor metabolism, Mice, Polymorphism, Single Nucleotide genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Quantitative Trait Loci genetics, Regulatory Sequences, Nucleic Acid genetics, Ikaros Transcription Factor genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Children with Down syndrome have an approximately 10-fold increased risk of developing acute lymphoblastic leukemia and this risk is influenced by inherited genetic variation. Genome-wide association studies have identified IKZF1 as a strong acute lymphoblastic leukemia susceptibility locus in children both with and without Down syndrome, with association signals reported at rs4132601 in non-Down syndrome and rs58923657 in individuals with Down syndrome (r2 = 0.98 for these two loci). Expression quantitative trait locus analysis in non-Down syndrome lymphoblastoid cell lines has demonstrated an association between the rs4132601 risk allele and decreased IKZF1 mRNA levels. In this study, we provide further mechanistic evidence linking the region encompassing IKZF1-associated polymorphisms to pro-leukemogenic effects in both human lymphoblastoid cell lines and murine hematopoietic stem cells. CRISPR/Cas9-mediated deletion of the region encompassing the rs17133807 major allele (r2 with rs58923657 = 0.97) resulted in significant reduction of IKZF1 mRNA levels in lymphoblastoid cell lines, with a greater effect in Down syndrome versus non-Down syndrome cells. Since rs17133807 is highly conserved in mammals, we also evaluated the orthologous murine locus at rs263378223, in hematopoietic stem cells from the Dp16(1)Yey mouse model of Down syndrome as well as non-Down syndrome control mice. Homozygous deletion of the region encompassing rs263378223 resulted in significantly reduced Ikzf1 mRNA, confirming that this polymorphism maps to a strong murine Ikzf1 enhancer, and resulted in increased B-lymphoid colony growth and decreased B-lineage differentiation. Our results suggest that both the region encompassing rs17133807 and its conserved orthologous mouse locus have functional effects that may mediate increased leukemia susceptibility in both the Down syndrome and non-Down syndrome genetic backgrounds., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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