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

BMC Medical Genomics

Melanie A Carless¹  John Blangero¹  Greg R Collier²  Ken R Walder³  Shelley Cole¹  Vincent Diego¹  Harald H H Göring¹  Hemant Kulkarni¹ 

[1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA;Barwon Biotechnology, Geelong, VIC, Australia;Deakin University, Geelong, VIC, Australia

关键词: Omacetaxine;    Imatinib;    Gene expression;    Toxicity;    Microarray;    Chronic myeloid leukemia;   

Others  :  1134715
DOI  :  10.1186/1755-8794-5-37

 received in 2012-03-22, accepted in 2012-08-16,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Kulkarni et al.; licensee BioMed Central Ltd.

【 图 表 】

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