identifying genes that mediate anthracyline toxicity in immune cells

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ID: 243706
2015
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Ranked #185 of 333 articles by views in chemical research in chinese universities

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Abstract
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 = 5.01x10-8). 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. Thus, 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.
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efrick2015frontiersidentifying Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Amber eFrick;Oscar Takeo Suzuki;Cristina eBenton;Bethany eParks;Yuri eFedoriw;Yuri eFedoriw;Kristy eRichards;Kristy eRichards;Kristy eRichards;Russell eThomas;Russell eThomas;Tim eWiltshire;Tim eWiltshire
Journal chemical research in chinese universities
Year 2015
DOI
10.3389/fphar.2015.00062
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