Ancient DNA reveals possible origin of a racial/ethnic disparity in a childhood cancer

A genetic variant with Indigenous American ancestral origins may explain why more Hispanic/Latino children are diagnosed with acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia cells, stained pink-purple
Credit: Jacob Bledsoe, BCH
B-ALL cells

People who identify as Hispanic/Latino have the highest risk of a blood cancer called acute lymphoblastic leukemia (ALL) compared to other populations in the US, with 40 percent more Hispanic/Latino children being diagnosed than non-Hispanic white children.  However, the basis for this difference is not well understood. 

Researchers have identified a genetic variant in people with Indigenous American ancestry that may account for the increased risk of ALL in Hispanic/Latino children, who have more of this ancestry than other populations. The team analyzed ancient DNA and traced the variant all the way back to the first people to enter the Americas about 13,000 years ago.

"We were able to use genetic studies in diverse populations to identify this new risk factor that explains some of the population differences in ALL risk," says Vijay Sankaran, a lead author of the study, a physician-scientist at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and an associate member in the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard. The findings were published in Cell Genomics and are the result of a close collaboration with colleagues at the University of Southern California. 

Sankaran and colleagues employed genome-wide association studies GWAS to look for genetic mutations contributing to racial/ethnic differences in a subtype of ALL that affects the development of immune cells called B cells. The team discovered that the genetic variant reduces the expression of a gene called IKZF1, which encodes for a protein, Ikaros, that is required for B cell development. The researchers also found that the mutation is much less common in white non-Hispanic/Latino children.

Sankaran, postdoctoral fellow and first author Lara Wahlster, and their colleagues provide functional data that suggest the variant slows B cell maturation and, in turn, increases the chances of a cancerous mutation popping up in the cells. 

Self-identified Hispanic/Latino individuals in the United States are known to have diverse ancestral origins, including Indigenous American ancestry. The researchers found that this risk variant appeared to arise from Indigenous American ancestral origins and is nearly absent in people with predominantly European ancestry. This observation may explain the higher prevalence of ALL in some countries in Latin America, such as Mexico, where there is a greater contribution of Indigenous American ancestry, compared to countries like Argentina, where the contribution of that ancestry is much lower. 

The researchers then analyzed ancient DNA samples to understand when the risk variant arose in human history. The oldest previously sequenced ancient DNA from an Indigenous American individual, found at the Anzick site in Montana, carried the mutation. This means the risk variant was present among the first people who entered the Americas approximately 13,000 years ago. 

Further investigation revealed that the variant was promoted by natural selection. Sankaran and colleagues speculated that carrying the mutation may have protected people against infection since IKZF1 plays a role in immune function.

"Exploring ancient DNA provides insights into the roots of modern-day health differences, bridging the gap between our past and the pressing health challenges facing our society today," says Sankaran.

The study's findings may provide insights into the higher rates of treatment resistance and relapse observed in Hispanic/Latino children with ALL. Sankaran emphasizes the need for further research to gain a comprehensive understanding of the implications of this variant. Ultimately, Sankaran hopes this knowledge may lead to ways of preventing leukemia in children carrying the identified genetic variant.

"I hope our work will ultimately pave the path towards preventing this disease," says Sankaran.

Adapted from a press release issued by Dana-Farber/Boston Children's Cancer and Blood Disorder Center.


This study was funded by the National Cancer Institute, the New York Stem Cell Foundation, the Leukemia & Lymphoma Society, and the Dana-Farber Cancer Institute Presidential Priorities Initiative.

Paper cited

De Smith AJ, Wahlster L, Jeon S, et al. A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell Genomics. Online March 26, 2024. DOI: 10.1016/j.xgen.2024.100526.