Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines
Hemant KulkarniHarald H.H. GöringVincent P. DiegoShelley ColeKen WalderGreg R. CollierJohn BlangeroMelanie A. Carless
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Abstract:
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. 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. 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). 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.Keywords:
Imatinib Mesylate
Objective: To screen the differential expression genes of Kanglaite Injection in treating cancer cachexia. Methods: mRNA was extracted from the blood cells of T739 animal model of C.C., hybridizated respectively on 20S gene chip. Analysis discuss on differential expression genes was carried out. Results: 5 differential expression genes were obtained. Among these genes, 4 genes were up-regulated and 1 gene was down-regulated. Most of these genes were related with immunity and metabolism of tumor. Conclusion: cDNA microarray for analysis of gene expression patterns is a powerful method to identify associated genes of Kanglaite.
Cancer Cachexia
Gene chip analysis
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The BCR-ABL fusion gene product is a constitutively activated tyrosine kinase, which is fundamental in the pathogenesis of chronic myeloid leukemia (CML). Imatinib mesylate (imatinib, Glivec® or Gleevec®), a small molecule inhibitor of the BCR-ABL tyrosine kinase, is now the first-line treatment for all newly diagnosed chronic phase CML patients. Imatinib treatment results in a high frequency of complete cytogenetic response (CCgR). Patients in CCgR can be further stratified by the degree of minimal residual disease, measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The present thesis deals with different aspects on molecular monitoring of imatinib treated CML patients. By serially analyzing peripheral blood and bone marrow BCR-ABL transcript levels using qRT-PCR in CML patients commencing imatinib therapy, we found that the major decline in BCR-ABL transcripts occurred within 6 months after start of imatinib treatment. An apparent plateau in BCR-ABL transcript level seems to have been reached after 12-15 months of imatinib treatment, which indicates a stable number of remaining BCR-ABL positive cells. To search for markers associated with molecular response in CML patients treated with imatinib, we studied the mRNA expression of apoptosis-related genes in peripheral blood nucleated cells from chronic phase CML patients commencing imatinib treatment. We found that a lower BAD expression at diagnosis correlates with a better molecular response at 12 months of imatinib therapy. Studies of BCR-ABL kinase domain mutations in imatinib treated CML patients revealed that point mutations were mainly associated with acquired resistance, but not with cytogenetic or molecular disease persistence in CML patients without signs of increasing leukemia burden. Finally we studied “off-target” effects of imatinib on peripheral blood on T-lymphocytes. We found that therapeutic doses of imatinib alter the expression of apoptosis related genes in CD3+ lymphocytes and change the phenotype of CD4+CD28+ T-helper cells.
Imatinib Mesylate
Chronic myelogenous leukemia
ABL
breakpoint cluster region
Minimal Residual Disease
Philadelphia chromosome
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Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is a standard of care for chronic myeloid leukemia (CML). There are few publications on responses of patients with CML from the Indian subcontinent. This study analyzed the response rate, progression-free survival (PFS), overall survival (OS), and toxicities in patients with CML given imatinib. Analysis included patients with CML who received imatinib under the GIPAP program at our institution from January 2002 to December 2008. Standard criteria for hematological and cytogenetic responses were used. There were 400 patients, with a median follow-up of 47 months. One hundred and seventy received prior non-imatinib therapy and 230 patients received imatinib upfront. Ninety-five percent of patients achieved complete hematological response. The cumulative best rate of major cytogenetic response was 72%, with 53% complete cytogenetic response and 19% partial cytogenetic response. The estimated PFS and OS at median follow-up for the whole group was 76% and 94%, respectively. Differences in PFS and OS in prior non-imatinib and upfront imatinib groups were not statistically significant. However, better PFS and OS were seen in the upfront imatinib group. Imatinib was well tolerated in our study.
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Chronic myelogenous leukemia
Imatinib Mesylate
Philadelphia chromosome
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Imatinib mesylate is a targeted therapy that acts by inhibiting tyrosine kinase of the bcr-abl fusion oncoprotein, which is specific to chronic myeloid leukemia (CML), and the c-transmembrane receptor, which is specific to gastrointestinal stromal tumors. Interstitial pneumonitis is a rare adverse event of imatinib therapy. It is clinically difficult to distinguish from infectious pneumonia, which can frequently occur due to the underlying disease. The standard treatment for imatinib-induced pneumonitis is to discontinue the medication and optionally administer corticosteroids. However, there are a few cases of successful retrial with imatinib. We describe a case of successful rechallenge of imatinib in a patient with imatinib-induced interstitial pneumonitis and CML without a recurrence of the underlying disease after 3 months of follow-up.
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Pneumonitis
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Evolutionary rates provide important information about the pattern and mechanism of evolution. Although the rate of gene sequence evolution has been well studied, the rate of gene expression evolution is poorly understood. In particular, it is unclear whether the gene expression level and tissue specificity influence the divergence of expression profiles between orthologous genes. Here we address this question using a microarray data set comprising the expression signals of 10,607 pairs of orthologous human and mouse genes from over 60 tissues per species. We show that the level of gene expression and the degree of tissue specificity are generally conserved between the human and mouse orthologs. The rate of gene expression profile change during evolution is negatively correlated with the level of gene expression, measured by either the average or the highest level among all tissues examined. This is analogous to the observation that the rate of gene (or protein) sequence evolution is negatively correlated with the gene expression level. The impacts of the degree of tissue specificity on the evolutionary rate of gene sequence and that of expression profile, however, are opposite. Highly tissue-specific genes tend to evolve rapidly at the gene sequence level but slowly at the expression profile level. Thus, different forces and selective constraints must underlie the evolution of gene sequence and that of gene expression.
Molecular evolution
Sequence (biology)
Rate of evolution
Divergence (linguistics)
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Objective To analyze the differential gene expression profiling of liver in rats subjected to hemorrhagic shock(HS) and sham hemorrhage shock(SHAM) by gene chip technology, thus to evaluate the possible molecular pathogenesis of HS. Method 20 male Wistar rats were randomly divided into a SHAM group and a HS group, with 10 rats in each group. Hepatic gene expression profiles were detected by oligonucleotide microarrays of 5705 mouse genes in two groups for three times. Genes with ratio(R) > 2 were identified as up-regulated and R < 0.5 were identified as down-regulated. Biological function of differentially expressed genes was analyzed and 9 genes were selected to undergo semi-quantitative RT-PCR. Results Among the total 5705 probes detected,86 genes showed differential expression in HS group comparison with SHAM group. The expression levels of 72 genes were up-regulated while those of 14 genes were down-regulated significantly. Differentially expressed genes were classified according to their biological function: transport genes, transcription regulator genes, signaling genes, response to stress genes, metabolic genes, development genes and cell adhesion genes. Conclusions cDNA microarray is an efficient and high-throughout method to survey gene expression profiles in HS.The variation of those gene expressions might be a potential pathogenic mechanism for HS that may offer a novel target for further study of therapeutic strategies of HS.
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Hemorrhagic shock; DNA chip; Gene expression; liver
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Abstract Chronic neutrophilic leukemia (CNL) is a rare hematologic disorder, for which there is no standard therapy. Recently, STI (imatinib mesylate) has been shown to be effective in treating patients with chronic myeloproliferative disorder (CMPD) displaying the translocation of the PDGFβR gene. Here, we present a case of a patient with CNL carrying t(15;19)(q13;p13.3) who achieved a cytogenetic remission following treatment with imatinib, 400 mg daily. After failure of alpha interferon and hydroxyurea therapy, a durable and complete clinical and cytogenic remission was induced by imatinib. To our knowledge, this is the first case with CNL who showed complete response with cytogenic remission after treatment of imatinib. The mechanism of response to this molecule is unknown in our case (other oncogenes than c‐kit, tyrosine kinase, or PDGFR may be involved). The patient remains in complete remission with an excellent performance status after 7 months of therapy. We demonstrate here that imatinib can induce a clinical and cytogenetic response in a case of CNL associated with a novel translocation other than a 5q33 rearrangement. Further studies including the molecular cloning of the t(15;19)(q13;p13.3) will be important in understanding the pathophysiology of CNL with a heterogeneous clinical course and the exploitation of the basic mechanisms of imatinib treatment. Am. J. Hematol. 77:366–369, 2004. © 2004 Wiley‐Liss, Inc.
Imatinib Mesylate
Philadelphia chromosome
breakpoint cluster region
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Imatinib Mesylate
Targeted Therapy
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Chronic myelogenous leukemia
Imatinib Mesylate
Hematology
ABL
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