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

Kulkarni, Hemant, Goring, Harald H. H., Diego, Vincent, Cole, Shelley, Walder, Ken R., Collier, Greg R., Blangero, John and Carless, Melanie A. 2012, Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines, BMC medical genomics, vol. 5, Article no. 37, pp. 1-12.

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Title Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines
Author(s) Kulkarni, Hemant
Goring, Harald H. H.
Diego, Vincent
Cole, Shelley
Walder, Ken R.
Collier, Greg R.
Blangero, John
Carless, Melanie A.
Journal name BMC medical genomics
Volume number 5
Season Article no. 37
Start page 1
End page 12
Total pages 12
Publisher BioMed Central Ltd
Place of publication London, England
Publication date 2012
ISSN 1755-8794
Keyword(s) Chronic myeloid leukemia
Omacetaxine
Imatinib
Gene expression
Toxicity
Microarray
Summary 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.
Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Language eng
Field of Research 111201 Cancer Cell Biology
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2012, Kulkarni et al.; licensee BioMed Central Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30050939

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.