Identifying genes that mediate anthracyline toxicity in immune cells.
The role of the immune system in response to chemotherapeutic agents remains elusive. The interpatient variability observed in immune and chemotherapeutic cytotoxic responses is likely, at least in part, due to complex genetic differences. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at identifying genes underlying these chemotherapeutic cytotoxic effects on immune cells. Using genome-wide association studies (GWAS), we identified four genome-wide significant quantitative trait loci (QTL) that contributed to the sensitivity of doxorubicin and idarubicin in immune cells. Of particular interest, a locus on chromosome 16 was significantly associated with cell viability following idarubicin administration (p = 5.01 × 10(-8)). Within this QTL lies App, which encodes amyloid beta precursor protein. Comparison of dose-response curves verified that T-cells in App knockout mice were more sensitive to idarubicin than those of C57BL/6J control mice (p < 0.05). In conclusion, the cellular screening approach coupled with GWAS led to the identification and subsequent validation of a gene involved in T-cell viability after idarubicin treatment. Previous studies have suggested a role for App in in vitro and in vivo cytotoxicity to anticancer agents; the overexpression of App enhances resistance, while the knockdown of this gene is deleterious to cell viability. Further investigations should include performing mechanistic studies, validating additional genes from the GWAS, including Ppfia1 and Ppfibp1, and ultimately translating the findings to in vivo and human studies.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, NC, USA.
Amber
A
Frick
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, NC, USA.
Oscar T
OT
Suzuki
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, NC, USA.
Cristina
C
Benton
The Hamner Institutes for Health Sciences, Research Triangle Park NC, USA.
Bethany
B
Parks
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina Chapel Hill, NC, USA ; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina Chapel Hill, NC, USA.
Yuri
Y
Fedoriw
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina Chapel Hill, NC, USA ; Department of Genetics, School of Medicine, University of North Carolina Chapel Hill, NC, USA.
Kristy L
KL
Richards
The Hamner Institutes for Health Sciences, Research Triangle Park NC, USA ; National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park NC, USA.
Russell S
RS
Thomas
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, NC, USA ; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina Chapel Hill, NC, USA.
Tim
T
Wiltshire
amyloid precursor protein; anthracyclines; candidate genes; genome-wide association studies; immune cells; pharmacogenomics