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Childhood Leukemia Study Leads to Ancient Variant Linked to Population-Specific Risk

NEW YORK – A team from Boston Children's Hospital, the University of Southern California, and elsewhere has delved into the outsized acute lymphoblastic leukemia (ALL) incidence previously described in individuals with self-reported Hispanic or Latino ancestry.

"While it was known that there was a higher incidence of childhood leukemia (acute lymphoblastic leukemia) in Hispanic/Latino children in the US compared to non-Hispanic/Latino children, the precise basis of this has remained unknown," co-senior and co-corresponding author Vijay Sankaran, a hematology/oncology researcher affiliated with Boston Children's Hospital and Dana-Farber Cancer Institute, said in an email.

With their new analyses, published in Cell Genomics on Tuesday, he and his colleagues identified and started characterizing a noncoding regulatory variant associated with childhood ALL risk in Hispanic/Latino individuals that stemmed from sequences inherited from Indigenous American ancestry.

With the help of data on thousands of cases and controls from a trans-ancestry genome-wide association study that members of the same team published in 2022, the researchers used statistical fine-mapping to find a variant in and around a chromosome 7 site near the IKAROS family zinc finger-coding gene IKZF1 that was linked to childhood ALL risk in Hispanic/Latino individuals.

The locus did not show ties to childhood ALL in non-Hispanic White participants, they noted, but was associated with roughly a 1.4-fold rise in ALL risk in the Hispanic/Latino participants.

Meanwhile, by bringing in published whole-genome sequencing data, as well as blood RNA-seq data for participants in the "Genes-environments and Admixture in Latino Asthmatics" and "Study of African Americans, Asthma, Genes, and Environments" studies, the team searched for ALL risk SNPs in the region that had expression quantitative trait locus (eQTL) effects on IKZF1 gene expression.

Together, the data pointed to an apparent causal variant in an enhancer sequence downstream of IKZF1, the researchers reported. Their subsequent selection and ancestry analyses suggested that variant coincided with Indigenous American ancestry — turning up in the heterozygous form in the sequenced Anzick individual — and may have conferred a selective advantage in the past.

"A few potential risk loci have been described, but now we identify a new risk variant that appears to explain a considerable amount of this risk," Sankaran said. "Importantly, we also start to define the mechanisms through which this variant might act to impact how immune cell development occurs and how this was altered in the course of human history."

In particular, the team's subsequent chromatin accessibility analyses — which included single-cell ATAC-seq experiments and ATAC-seq profiling on B-cells from 156 ALL patients — further suggested the enhancer variant not only interacts with the IKZF1 promoter but is also particularly active in B-cell precursors from the so-called "pro-B" stage of B-cell development.

Together, the current study "demonstrates the molecular and evolutionary mechanisms through which a single genetic variant that impacts gene regulation explains a considerable portion of the disparity in ALL risk in Hispanic/Latino children," the authors suggested, "while also uncovering mechanisms through which such risk can arise."

"Further research is warranted to fully understand the contribution of genetic variation to this disparity in ALL incidence and how this can impact other clinical endpoints beyond the risk of developing ALL that demonstrate racial/ethnic disparities," they added, "such as overall survival, risk of relapse, and cytokine release syndrome with CAR T-cell therapy."