A new study, published in the American Journal of Human Genetics, has reported that genetically induced shifts in blood cell ratios can increase an individual’s risk of developing acute lymphoblastic leukaemia. The team’s findings have the potential to influence future cancer treatments.
Acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia (ALL) is the most common cancer in children under 15 years of age. In ALL, the body releases immature white blood cells in large numbers from the bone marrow. This event reduces the number of healthy red blood cells in the individual. It also weakens the immune system, making the patient more prone to infection.
Despite recent advances in treatment, ALL remains one of the leading causes of paediatric cancer mortality in the USA. Previous studies have found that there is overlap between genetic risk loci for ALL and other haematologic traits. However, scientists still don’t know whether dysregulated blood-cell homeostasis contributes to ALL risk. As a result, a deeper understanding of the underlying causes of ALL is critical to develop new and effective treatments.
In this study, researchers used data from the UK Biobank to carry out a genome-wide association study (GWAS) of childhood ALL as well as a GWAS of blood cell traits. They aimed to uncover whether any causal effects of variation in blood cell homeostasis impacted ALL susceptibility.
Blood cell ratios associated with leukaemia
The genome-wide analyses identified significant correlations between ALL risk and blood cell levels. The researchers observed a positive correlation between ALL risk and lymphocyte levels, neutrophil levels and lymphocyte-to-monocyte ratio (LMR). In contrast, increased platelet-to-lymphocyte ratio (PLR) corresponded with lower ALL risk.
In addition, the team conducted Mendelian randomisation analyses on the GWAS data to investigate if the observed correlations were causal. The analyses indicated that genetically predicted increases in LMR were associated with an approximately 22% increase in ALL risk. Interestingly, predicted increases in neutrophil-to-lymphocyte ratio (NLR) and PLR were both associated with a lower risk of developing ALL. These results suggest that individuals with a genetic predisposition to shifts in blood cell ratios are more likely to develop ALL.
Variants associated with ALL
Next, the researchers set out to uncover the variants underlying ALL. Amazingly, the team identified two variants significantly associated with ALL.
The first variant identified was on chromosome 2q22.1, near the CXCR4 gene, which encodes a chemokine receptor. Interestingly, previous studies have found that metastatic breast cancer and bone metastases have higher levels of CXCR4 gene expression. In this study, the researchers found the variant to specifically affect both NLR and whole-blood gene expression of MCM6. Like CXCR4, previous work has shown that multiple cancer patients have upregulated expression of MCM6. As MCM6 is involved in DNA regulation and activation of cell signalling pathways, these results suggest these mechanisms may play a role in driving ALL.
The second variant discovered by the team was in the FLT3 gene, which encodes a receptor tyrosine kinase that serves as a key regulator of haematopoiesis. This variant is of particular interest as it has very recently been associated with an increased risk of autoimmune thyroid disease and acute myeloid leukaemia (AML). Additional studies will be required to further investigate the role of FLT3 in ALL.
Conclusions and future work
Overall, the key finding from this study is that genetically induced shifts towards high lymphocyte counts can result in higher childhood ALL risk. In addition, the identification of variants significantly associated with ALL provides potential targets for future treatments. In fact, researchers are currently investigating CXCR4 as a therapeutic target in both ALL and AML.
This study does have some limitations. The data in this study was obtained from the UK Biobank. Therefore, the findings are biased towards individuals with predominantly European ancestry. In the future, more diverse populations should be studied. In addition, the team suggest that in future studies, the subpopulations of B cell and T cell lymphocytes should be distinguished from each other. The most common ALL subtype is B cell precursor ALL, which is likely to have distinct mechanisms from T cell ALL.
Despite these limitations, this study has identified important genetic mechanisms underlying ALL. These findings will hopefully pave the way for future research into ALL diagnosis and treatment.
Image by Gerd Altmann from Pixabay