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 journalArticle

10 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Gene Expression
Cell Line
Therapeutics
Pharmaceutical Preparations
Imatinib Mesylate
homoharringtonine
Pedigree
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Vacuoles
Cell Division
Genes
Cluster Analysis
Cell Survival
Phosphotransferases
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines. / Kulkarni, Hemant; Göring, Harald H H; Diego, Vincent; Cole, Shelley; Walder, Ken R.; Collier, Greg R.; Blangero, John; Carless, Melanie A.

In: BMC Medical Genomics, Vol. 5, 37, 2012.

Research output: Contribution to journalArticle

Kulkarni, Hemant ; Göring, Harald H H ; Diego, Vincent ; Cole, Shelley ; Walder, Ken R. ; Collier, Greg R. ; Blangero, John ; Carless, Melanie A. / Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines. In: BMC Medical Genomics. 2012 ; Vol. 5.
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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.",
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T1 - Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

AU - Kulkarni, Hemant

AU - Göring, Harald H H

AU - Diego, Vincent

AU - Cole, Shelley

AU - Walder, Ken R.

AU - Collier, Greg R.

AU - Blangero, John

AU - Carless, Melanie A.

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N2 - 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.

AB - 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.

KW - Chronic myeloid leukemia

KW - Gene expression

KW - Imatinib

KW - Microarray

KW - Omacetaxine

KW - Toxicity

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