Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines.
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.
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA. hkulkarn@txbiomedgenetics.org
Hemant
H
Kulkarni
Harald H H
HH
Göring
Vincent
V
Diego
Shelley
S
Cole
Ken R
KR
Walder
Greg R
GR
Collier
John
J
Blangero
Melanie A
MA
Carless
D001549:Benzamides; D002460:Cell Line; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006248:Harringtonines / Q000633:toxicity*; D000077863:Homoharringtonine; D006801:Humans; D000068877:Imatinib Mesylate; D040582:Inheritance Patterns / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D015203:Reproducibility of Results
D001549:Benzamides; D006248:Harringtonines; D010879:Piperazines; D011743:Pyrimidines; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate