Gene Variant Raises ALL Risk in Hispanic/Latino Children

Microscopic images of red blood cells, activated platelets, and white blood cells as a result of leukemia: © AkuAku - stock.adobe.com

A study conducted at the Keck School of Medicine at the University of Southern California (USC) shed light on the higher risk of acute lymphoblastic leukemia (ALL) in Hispanic/Latino children compared with non-Hispanic White children.

Researchers, including the study’s lead author Adam de Smith, PhD, identified a specific genetic variant on the IKZF1 gene that increases ALL risk by 1.4 times and is more frequent in people of Hispanic/Latino descent. While this variant is found in about 30% of Hispanic/Latinos, it’sobserved in less than 1% of non-Hispanic Whites.

de Smith and his team identified that the variant reduces IKZF1 protein expression, potentially hindering B-cell development and increasing the risk of mutations leading to ALL.

This discovery has the potential to lead to improved screening tools for ALL, and understanding how the variant affects B-cells could guide new treatment strategies. Further research is warranted to explore the variant's impact on treatment outcomes and ALL risk in Hispanic/Latino adolescents and young adults.

In an interview with Targeted Oncology^TM, de Smith, assistant professor of population and public health sciences, Keck School of Medicine of USC, discussed the study and the implications this disparity has for the Hispanic/Latino patient population.

Targeted Oncology: What are some of the unmet needs in this patient population that the study focused on?

de Smith: Children of self-reported Hispanic/Latino ethnicity in the United States have about a 1.3-, 1.4-fold increased risk of acute lymphoblastic leukemia compared with non-Hispanic White children. Also, Hispanic/Latino patients have inferior outcomes than non-Hispanic White patients. If we want to alleviate this disparity, we need to understand the causes of it. A handful of germline genetic variants had previously been implicated in the increased risk of ALL in Hispanic/Latino individuals. But we believe that there were likely additional variants that contribute to this disparity.

Could you discuss some of the methodology for your analysis?

In our study based in California, it includes over 1800 Hispanic/Latino ALL cases and about 8000 controls. Then, we also have case-control data from other populations, including non-Hispanic Whites and East Asians. Using these data, we performed something called genetic fine-mapping. In this study, we particularly focused on the gene IKZF1, or Ikaros as it's also known. We focused on this because it's an important risk gene for ALL, and previous studies had suggested that there were multiple independent genetic associations across this gene. But this had not been comprehensively studied before. By doing the genetic fine-mapping, we are testing for how many independent associations are there. And by doing this, we found that in Hispanics/Latinos, we found 3 of these risk variants, whereas in non-Hispanic Whites and East Asians, there are only 2. Hispanics/Latinos appear to be unique in having 3 independent risk factors at IKZF1.

One of these was newly discovered and had a risk allele frequency of about 18%, which translates to a carrier frequency of about 30% in Hispanics/Latinos. About 30% of the Hispanic/Latino population in the US would carry this allele. It was also rare in individuals of predominantly European ancestry, so fewer than 1%.

Next, we assessed the association of this allele with genetic ancestry and found that it was positively correlated with indigenous American ancestry among Hispanics/Latinos. We found this looking at both global ancestry and locally at the haplotype level. This motivated us to look at ancient DNA samples across the Americas to test when that risk allele may have first arisen. We analyzed sequencing data and found that the oldest indigenous American individual carried that risk allele, which supports that it first arose at least 13,000 years ago.

We think that it was brought to the Americas when the original population came across the Bering Strait. Because the risk allele frequency is much higher in modern day indigenous American populations, as well as being higher in Hispanic/Latino individuals, we were interested to see if there was evidence of selection. We tested that and indeed found in Hispanics/Latinos that this risk allele appears to have been selected for, so we think it conferred some adaptive advantage.

We used various methods to investigate the functionality of this variant. We tested its association with gene expression and with chromatin accessibility. In collaboration with Vijay Sankaran [MD, PhD] at Boston Children's Hospital and the Broad Institute, we investigated functional effects of the variant and of the enhancer region within which this variant resides.

Could you discuss your hypothesis on selection?

We found evidence of positive selection of this IKZF1 allele. Then the question was why might this have been selected for? Our hypothesis, which obviously we need to test, is that when Europeans first colonized the Americas, they brought overall these different infections and diseases that wiped out much of the indigenous populations. We think perhaps, this IKZF1 variant may have conferred some selective advantage in the face of these infections, like improving immune response for example, but on the flip side, may have increased childhood leukemia risk. But because childhood leukemia is thankfully so rare, the negative effects of that allele would not have cancelled out the positive effect on the benefits to the immune system in the face of these new infections. Fast forward several hundred years, this allele rose to a certain frequency in Hispanic/Latino populations, through admixture with European as well as African populations.

What are some of the effects this variant has in the development of ALL?

We identified the putative causal variant, which was within an enhancer region downstream of the IKZF1 gene. Now, IKZF1, I mentioned, was a known ALL risk gene. It is also an important transcription factor for lymphoid development, and loss of IKZF1 is common in ALL at diagnosis. It’s been shown that loss of IKZF1 blocks B-cell development at an early stage where the cells have a high proliferative potential and are likely more susceptible to malignant transformation.

Back to the variant, we found that it was associated with reduced expression of IKZF1, and we think that this may be specific to B cells, because we showed that the enhancer region is very much mostly active in early B cells. We think the variant may lead to stalled B-cell development, which could increase the risk of developing ALL, for example, through increased chances of developing somatic mutations, such as through off-target VDJ recombination, which is known to be a driver of somatic alterations in ALL. That’s something we'd like to work on next, delve more into precisely how the impactof 1 variant may increase ALL risk.

What was the rationale of focusing on pediatric patients in this study?

That is an important question. The rationale for focusing on pediatric ALL is because ALL is much more common in children. It is the most common cancer in children. But it is important to point out that the disparity in risk that affects Hispanics/Latinos continues into adult life. As I mentioned previously, children have about a 1.3-to 1.4-fold increased risk. When you get to the Hispanic/Latino adolescent young adult and to older adult populations, they have about a 2-fold increased risk of ALL compared with non-Hispanic White adults, so it is an even greater disparity.

The reason that we did not investigate the genetic risk is that currently there really is not much data available or samples available to study adult ALL. But that is something that I am hoping to expand our research on. This IKZF1 variant would be particularly interesting to look at in the Hispanic/Latino adult population to see if it also contributes to the increased ALL risk there.

Are there any other genetic variants being explored across leukemia types that are specific to certain ethnic or racial groups?

I would say that is to be determined. There have been other variants implicated in the increased ALL risk in Hispanics/Latinos, such as GATA3 gene and ARID5B. But we are currently working on putting together all of the available germline genetic data in Hispanic/Latino ALL studies and generating some new data. We hope that this might reveal novel risk variants and other genes that may explain the disparity in ALL risk in Hispanic/Latino individuals in the United States.

REFERENCE:

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