A genetic variant located on the IKZF1 gene may be responsible for disparities in the risk of acute lymphoblastic leukemia (ALL) among Hispanic and Latino children, according to a recent study published by de Smith et al in Cell Genomics. The findings offer insights into the causes of the disease in this patient population.
Background
ALL is the most common type of cancer in pediatric patients. In the United States, the disease disproportionately affects Hispanic and Latino children—who are 30% to 40% more likely to develop ALL compared with non-Hispanic White children. However, the genetic basis and cause of the increased risk in this population are currently unknown.
The IKZF1 gene underlies B-cell development. Although the gene is known to be associated with ALL, it has not yet been linked with ethnic risk disparities.
“Combined with the fact that around 30% of Hispanic [and] Latino [individuals] in the United States carry this gene variant, but it’s basically absent in [those] of predominantly European ancestry, we think it's an important contributor to the increased ALL risk among this group,” revealed lead study author Adam de Smith, PhD, Assistant Professor of Population and Public Health Sciences and a member of the Norris Comprehensive Cancer Center at the Keck School of Medicine at the University of Southern California (USC) as well as a scholar at the Leukemia & Lymphoma Society.
Study Methods and Results
In the recent study, researchers used the California Cancer Records Linkage Project to analyze the genetic data of 10,289 pediatric Hispanic and Latino patients with (n = 1,878) and without (n = 8,411) ALL, 58,503 pediatric non-Hispanic White patients with (n = 1,162) and without (n = 57,341) and without ALL, and 5,335 pediatric East Asian patients with (n = 318) and without (n = 5,017) ALL.
Using genetic fine-mapping analysis to disentangle the separate effects of genetic variants in a region of the genome, the researchers independently analyzed each single-nucleotide polymorphism along the IKZF1 gene to determine whether having a certain variant increased the risk of ALL. They identified three independent single-nucleotide polymorphisms linked to higher ALL incidence—one of which was present in about 30% of the Hispanic and Latino patients and less than 1% of the non-Hispanic White patients. Although the overall risk for the disease was low across all racial and ethnic groups, the patients with the IKZF1 gene variant, located at the single-nucleotide polymorphism rs76880433, were 1.44 times more likely to develop ALL compared with the patients without the variant.
The genetic ancestry of most Hispanic and Latino individuals can be traced to Europe, Africa, and Indigenous America. The researchers revealed that the risk variant was specifically linked with Indigenous American ancestry and may have become more common in this group because it may have conferred a selective advantage at some point during human history.
The researchers next sought to better understand how the IKZF1 gene variant may be related to ALL through its influence on the development of B cells. They conducted a test to analyze chromatin accessibility and found that the IKZF1 gene variant reduced accessibility and prevented IKZF1 proteins from being fully expressed. The researchers also evaluated stem cells and uncovered that knocking out the IKZF1 gene caused B-cell development to stall in its early stages.
“Looking at all of this together, we think that the risk variant is reducing IKZF1 expression. By doing so, it’s keeping B cells in a more immature state, which would increase ALL risk by giving the cells more chance to develop mutations that could eventually lead to overt leukemia,” stressed Dr. de Smith.
Conclusions
“Together, the analyses in our study provide the statistical, biological, and evolutionary insights behind this increased risk, and may ultimately aid [researchers] working to develop screening tools and therapies for ALL,” highlighted co–senior study author Charleston Chiang, PhD, Associate Professor of Population and Public Health Sciences and Associate Director of the Center of Genetic Epidemiology at the Keck School of Medicine at USC.
The researchers indicated that their recent findings could bring them closer to developing effective screening tools to predict which patients may develop ALL and may provide critical insights into novel treatment strategies like progressing B-cell development after a stall. They plan to further explore whether the newly identified risk variant may help explain the higher risk of ALL among Hispanic and Latino adolescents and young adults who are more than twice as likely to develop the disease compared with non-Hispanic White individuals.
“We also need to understand whether this variant is associated with different patient outcomes such as the risk of relapse or chances of survival and why that might be,” Dr. de Smith concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the New York Stem Cell Foundation, and the Dana-Farber Cancer Institute Presidential Priorities Initiative. For full disclosures of the study authors, visit cell.com.
