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Study Finds Genetic Predisposition to Higher Lymphocyte Production May Lead to Higher ALL Risk


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Research published by Kachuri et al in the American Journal of Human Genetics reveals that children born with a genetic predisposition to produce more lymphocytes—particularly in relation to other types of white blood cells—may be at a higher risk of developing acute lymphoblastic leukemia (ALL). This finding could help in the development of risk models for newborns that could lead to early intervention strategies.

“I hope that our research will be able to help to identify children at birth who have the highest risk of leukemia,” said corresponding study author Adam de Smith, PhD, Assistant Professor in the Center for Genetic Epidemiology at the Keck School of Medicine of the University of Southern California (USC) and a member of the USC Norris Comprehensive Center. “An ideal goal would be if newborn screenings in the future could incorporate screening for preleukemia.”

Adam de Smith, PhD

Adam de Smith, PhD

Past genetic studies identified over a dozen locations on the genome associated with childhood ALL. Noting these spots matched places on the genome associated with variations in blood cell traits, such as white blood cell counts, the research team was inspired to investigate a connection between overproduction of lymphocytes and the risk of developing ALL.

Overproduction of Lymphocytes

The study found that children who are genetically predisposed to producing high amounts of lymphocytes have a 20% or more increased risk of developing ALL. The study also shed light on the significance of the number of lymphocytes in proportion to other key blood cells.

“Ours was the first study to look for genetic variations associated with the ratio of lymphocytes to certain other blood cells—the ratio of lymphocytes to monocytes, the ratio of lymphocytes to neutrophils, and the ratio of lymphocytes to platelets,” said Dr. de Smith. “It seems that it’s not just the genetic propensity to produce large numbers of lymphocytes, but it’s how those numbers relate to other blood cell types as well.”

Drawing from UK Biobank data from over 400,000 individuals, the researchers conducted a two-stage genome-wide association study of blood cell traits, followed by analysis in 2,666 cases of ALL and more than 60,000 controls. Data from the UK Biobank is from adults of European ancestry, but in the United States, Latinx children in particular are at higher risk of developing ALL than non-Latinx children.

The USC study outlines two hypotheses of how overproduction of lymphocytes could play a role in the events leading to leukemia. Children who are genetically predisposed to lymphocyte overproduction have an increased pool of preleukemic cells, and, subsequently, elevated chances of a secondary mutation occurring. A separate, but not mutually exclusive, hypothesis is that the overproduction of lymphocytes could factor into why the immune system fails to respond normally to infection in early life.

The researchers’ theories correspond with the prevailing “delayed infection” theory of childhood leukemia and current research in preventing the onset of the disease. If children are not exposed enough to infections and microbes as infants, their immune systems may not be primed properly. To that end, researchers are developing probiotics as well as other potential interventions to prevent the secondary mutations leading to ALL.

In the future, Dr. de Smith envisions that a risk score may be assigned to newborns based on genetic risk factors, including lymphocyte overproduction, as well as nongenetic risks, such as being born with a high birth weight or through a planned cesarean section. Children with high risk scores for ALL could receive early intervention therapies. 

In keeping with this line of inquiry, Dr. de Smith will be involved in leading the largest study to date using newborn cord blood cells to investigate preleukemic clones in utero. Detecting the presence of these cells could also eventually be part of routine newborn screening for ALL risk and, ultimately, preventive measures.

Disclosure: This study was supported by research grants from the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit cell.com/ajhg.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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