Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

Hemant Kulkarni, Harald H.H. Göring, Vincent Diego, Shelley Cole, Ken R. Walder, Greg R. Collier, John Blangero, Melanie A. Carless

    Research output: Contribution to journalArticlepeer-review

    10 Scopus citations

    Abstract

    Background: Imatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime. Methods. We conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure. Results: Cytotoxicity within cell lines was highly heritable following imatinib treatment (h2=0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly >10). Conclusions: Induction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background.

    Original languageEnglish (US)
    Article number37
    JournalBMC Medical Genomics
    Volume5
    DOIs
    StatePublished - 2012

    Keywords

    • Chronic myeloid leukemia
    • Gene expression
    • Imatinib
    • Microarray
    • Omacetaxine
    • Toxicity

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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