Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, caused by an overgrowth of immune cells. Hispanic children in the US are about 1.5 times more likely to get ALL and more likely to have a severe case, even after controlling for socioeconomic factors. A team of researchers collected genetic data from diverse groups of ALL patients in California to identify a biological basis for this disparity. They narrowed it down to the gene IKZF1, a regulator of immune development, and a mutation that happened over 45,000 years ago, which spread through the Americas.

By correlating different genetic variants with ALL, these researchers found a distinct set of correlated variants in the IKZF1 gene associated with ALL risk. They only found this set when looking just at Hispanic children and not at other ethnicities. Together, with other variants in IKZF1 that are more common in Hispanic-Americans, these genetic signals explain some of the ALL risk disparity. They then employed a statistical method called “fine-mapping,” which narrows down a set of correlated variants to the few possible mutations that cause the biological change. After identifying the likely causal mutation in the Hispanic-specific signal, they found that it likely affects the activity of IKZF1 early in development. 

However, their findings are not the whole story. As the researchers state, the mutation they studied is also found in East Asian populations, but these populations do not experience a corresponding increase in ALL risk. They also traced the variant’s ~45,000 year history from the initial mutation and found that carrying this mutation might have been favorable by natural selection, but there is no straightforward reason why this might be. While this work is a huge step forward towards understanding the disparity in ALL risk, more work is still needed to parse through the genetic complexity of Indigenous American and Hispanic ancestry.

This study was led by Adam de Smith, an Assistant Professor of Population and Public Health Sciences at the University of Southern California, Lara Wahlster, a Pediatric Oncologist and Postdoctoral Fellow in Vijay Sankaran’s research group at Dana Farber Cancer Center, and Soyoung Jeon, as a PhD student in Cancer Biology and Genomics at the University of Southern California in Charleston Chiang’s research group.

Managing Correspondant: Alex Yerkin

Original Article:  A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children (Cell Genomics)

Press Article: Childhood Leukemia Study Leads to Ancient Variant Linked to Population-Specific Risk (Genome Web)

Image Source: Wikimedia

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