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Acute Lymphoblastic Leukemia Risk Linked to Genetically Mediated Increase in Lymphocyte Count

NEW YORK — A genetically mediated shift toward a higher lymphocyte count is associated with an increased risk of acute lymphoblastic leukemia in children, a new analysis has found.

ALL is the most common cancer among children under 15 years old and is thought to develop under a two-hit model, under which a preleukemic clone develops in utero and a second somatic mutation then spurs the development of leukemia.

While some genetic risk loci linked to ALL include variants in genes that have also been associated with hematopoiesis, lymphoid development, and blood-cell traits, researchers from the University of Southern California noted that the shared genetic architecture between childhood ALL and blood-cell traits has not been explored. In a paper appearing in the American Journal of Human Genetics on Tuesday, USC's Adam de Smith and his colleagues combined analyses of a genome-wide association study of children with ALL with a GWAS of blood-cell traits within the UK Biobank population.

"[W]e demonstrate that a genetic propensity for overproduction of lymphocytes, particularly in relation to other blood-cell types, is associated with an increased risk of childhood ALL in individuals of predominantly European ancestry," de Smith and his colleagues wrote in their paper.

Using data from the UK Biobank, the researchers conducted a two-stage GWAS of blood cell traits such as lymphocyte, platelet, and neutrophil counts, as well as neutrophil-to-lymphocyte ratios and platelet-to-lymphocyte ratios. About 3,000 genetic variants were associated with one or more of these hematological traits and explained between 4 percent and nearly 24 percent of the variation in those traits. Additionally, 115 loci were linked to blood-cell ratios.

The researchers then examined genetic links between these variants and ALL susceptibility by drawing on a cohort of 2,666 individuals with ALL and more than 60,000 controls. They uncovered positive correlations between increased lymphocyte counts, lymphocyte-to-monocyte ratio, and neutrophil levels with ALL risk, and an inverse correlation between a higher platelet-to-lymphocyte ratio and ALL risk.

Further, a Mendelian randomization analysis using the UK Biobank dataset found that a one-standard deviation increase in lymphocyte-to-monocyte ratio was linked to a 22 percent increase in ALL risk, while increases in platelet-to-lymphocyte ratio and neutrophil-to-lymphocytes ratio — both reflecting higher levels of other blood cell types than lymphocytes — were linked to lower ALL risk. The finding indicated to the researchers that genetically induced shifts toward higher lymphocyte counts were tied to an increased susceptibility for childhood ALL.

A clustering analysis identified two putative novel ALL risk variants from among those associated with blood cell traits, one on chromosome 2q22.1 and one within the FLT3 gene on 13q12.2. The researchers noted that variants within FLT3 have recently been linked to an increased risk of autoimmune thyroid disease and AML. The allele linked to both ALL and AML risk lead to a truncated FLT3 protein, but an increase in FLT3 ligand levels. While this variant has a greater effect on the development of myeloid cells, they said it could also affect ALL risk through its activation of the RAS/MAPK pathway.

The researchers noted their study has several limitations, including that the blood cell traits were measured in adult participants from the UK Biobank, as there is a dearth of GWAS of blood cell traits in children or newborns, as well as that their study focused on broad classes of cell types.

Going forward, they wrote, "[i]t will be important to elucidate the underlying biological mechanisms of our findings and to assess their transferability to admixed and non-European ancestry populations."

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