While the cure rates of childhood acute lymphoblastic leukemia (ALL) are approaching 85%, not all children benefit equally from this impressive progress. There are substantial differences in ALL outcome by race, with significantly higher relapse rates in Hispanics and blacks. The underlying causes of racial disparities in response to ALL therapy are largely elusive, while genetic and environmental factors may both be important. Preliminary results/rationale: In a preliminary study of 2,534 children with newly diagnosed ALL, we performed genome-wide association analysis to systematically identify germline genetic variations responsible for racial differences in ALL outcome. First, we demonstrated that genetically defined American Indian ancestry underlay the elevated rate of relapse in Hispanics across various treatment protocols. A subsequent genome- wide scan identified a cluster of genetic variations in the PDE4B gene with the strongest association with leukemia relapse risk (N=2,534, P=2.6W10-6). Importantly, the risk allele at the PDE4B SNP was 1.5 times more common in Hispanics than whites, contributing to the ancestry-related differences in ALL relapse risk. Genetic variation in PDE4B also exhibited association with other drug response phenotypes in ALL (minimal residual disease, glucocorticoid response and toxicity). Research objectives: Given the compelling evidence in support of the importance of PDE4B in ALL pharmacogenetics, the objectives of this application are to 1) systematically identify genetic variations in the PDE4B gene and characterize their contribution to racial differences in ALL treatment response, and 2) to establish laboratory models to mechanistically characterize PDE4B allelic variants and their role in racial differences in antileukemic drug response. Outcomes: Successful completion of these studies will firmly establish the importance of PDE4B in racial disparities in ALL outcome and encourage the development of PDE4B antagonists as a means of overcoming drug resistance in leukemia. Our long-term goal is to utilize knowledge on how genomic variation may explain racial disparities in ALL outcomes, so that we can implement personalized medicine via pharmacogenomics testing to improve the survival of children of all races with ALL.
For some cancers, there are substantial racial disparities in cure rates. Taking a pharmacogenetics approach, we propose to determine the contribution of genetic variations in the PDE4B gene to racial differences in cure rates for childhood leukemia, and how those gene variations affect racial differences in response to anti- leukemic medications. Long term, we aim to eradicate race/ethnicity differences in cure rates of childhood leukemia.
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