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Transcription profiling of human gastrointestinal stromal tumour is predictive of rapid response to imatinib mesylate

ABSTRACT: Gene expression profiling using oligonucleotide microarrays performed on tumor samples obtained before and after imatinib mesylate (IM) therapy. Rapid responding (to IM) samples were compared to non-responding/stable disease samples as measured by CT scan measurements to identify a gene signature that can predict rapid response to IM. Experiment Overall Design: 54 samples, 29 pre-treatment biopsy samples, 25 post-treatment/post-surgery tumor samples from Gastrointestinal Stromal Tumors

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Ochs

PROVIDER: E-GEOD-15966 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor.

Rink Lori L Skorobogatko Yuliya Y Kossenkov Andrew V AV Belinsky Martin G MG Pajak Thomas T Heinrich Michael C MC Blanke Charles D CD von Mehren Margaret M Ochs Michael F MF Eisenberg Burton B Godwin Andrew K AK

Molecular cancer therapeutics 20090811 8

Despite initial efficacy of imatinib mesylate in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant imatinib mesylate treatment for advanced primary and recurrent operable GISTs (Radiation Therapy Oncology Group S0132), gene expression profi ...[more]

PMID: 19671739

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Gene expression signature predictive of rapid response to imatinib mesylate in Gastrointestinal Stromal Tumor (GIST)

Project description:Gene expression profiling using oligonucleotide microarrays performed on tumor samples obtained before and after imatinib mesylate (IM) therapy. Rapid responding (to IM) samples were compared to non-responding/stable disease samples as measured by CT scan measurements to identify a gene signature that can predict rapid response to IM.

2009-11-24 | GSE15966 | GEO

Zebrafish liver transcriptome in response to chronic treatment with environmentally relevant concentrations of imatinib mesylate

Project description:Imatinib mesylate (IM) a protein kinase inhibitor drug that selectively inhibits certain oncogenic mutant protein tyrosine kinases. After application, IM is via hospital and municipal waste water effluents released into the aquatic environment, where it can harm non-target organisms. The aim of this study was to evaluate changes in gene transcription in liver of adult F1 zebrafish (Danio rerio) continuously exposed to IM at environmentaly relevant concentrations of 0.01 µg/L and 1 µg/L.

2019-11-05 | GSE84394 | GEO

Transcription profiling of juvenile Daphnia manga following exposure to various doses of Lufenuron, a benzoylphenylurea growth inhibitor (using Message Amp II)

Project description:Juvenile (<24hr old) Daphnia magna populations (n=25) were exposed (24hr) to 0.00ug, 0.15ug, 0.33ug, 0.65ug lufenuron Benzoylphenylurea growth inhibitor. Transcriptomic responses were screened using a D.magna cDNA microarray and the regulation of gene expression via log fold-change in transcript abundance, assessed. Genes involved in the synthesis of chitin were expected to respond to lufenuron, given the mode of action. Extracted total RNA was amplified (400ng/sample) prior to hybridisation with the expectation that this would increase the abundance of significantly responding genes.

2010-10-13 | E-TABM-797 | biostudies-arrayexpress

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2012-02-08 | GSE35559 | GEO

Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate

Project description:RATIONALE: Surgery may remove residual disease in patients with gastrointestinal stromal tumor that is responding to imatinib mesylate. It is not yet known whether surgery is more effective than continued imatinib mesylate in treating patients with metastatic gastrointestinal stromal tumor. PURPOSE: This randomized phase III trial is studying giving imatinib mesylate therapy together with surgery to see how well it works compared with imatinib mesylate alone in treating patients with metastatic gastrointestinal stromal tumor that is responding to imatinib mesylate.

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Gene expression profile induced by Imatinib

Project description:Activation-induced cytidine deaminase (AID) is essential for class switch recombination (CSR) and somatic hypermutation (SHM). Its deregulated expression acts as a genomic mutator that can contribute to the development of various malignancies. During treatment with imatinib mesylate (IM), patients with chronic myeloid leukemia (CML) often develop hypogammaglobulinemia, the mechanism of which has not yet been clarified. Here, we provide evidence that CSR upon B cell activation is apparently inhibited by IM through downregulation of AID. Furthermore, expression of E2A, a key transcription factor for AID induction, was markedly suppressed by IM. These results elucidate not only the underlying mechanism of IM-induced hypogammaglobulinemia but also its potential efficacy as an AID suppressor. We investigated that class switch recombination(CSR) upon B cell activation is apparently inhibited by imatinib mesylate(IM) through downregulation of activation-induced cytidine deaminase(AID). Furthermore, expression of E2A was markedly suppressed by IM. To elucidate the more detailed pathway, we performed the microarray analysis. Microarray analysis was performed on splenocytes cultured for 72 h in the presence or absence of 10 µM Imatinib. The mouse splenocytes were cultured for 72 h with or without 10 µM Imatinib (IM) in conditioning medium containing IL-4 and LPS. RNA from 1X10^6 splenocytes used for microarray analysis was isolated using the RNeasy Mini Kit (50) (Qiagen, Hilden, Germany).　Gene expression microarray analysis was performed using one-color microarray-based gene-expression analysis (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer’s instructions. After scanning, expression values for the genes were determined using GeneSpringGX software.

2012-02-08 | E-GEOD-35559 | biostudies-arrayexpress

Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate

Project description:The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.

2011-03-15 | GSE23946 | GEO

Imatinib therapy of chronic myeloid leukemia restores the expression levels of key genes for DNA damage and cell cycle progression

Project description:Background: Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. It is well known that CML cells are genetically unstable. However, the mechanisms by which these cells acquire genetic alterations are poorly understood. Imatinib mesylate (IM) is the standard therapy for newly diagnosed CML patients. IM targets the oncogenic kinase activity of BCR-ABL. Objective: To study the gene expression profile of BM hematopoietic cells in the same patients with CML before and one month after imatinib therapy. Methods: Samples from patients with CML were analyzed using Affymetrix GeneChip Expression Arrays. Results: A total of 594 differentially expressed genes, most of which (393 genes) were downregulated, as a result of imatinib therapy were observed. Conclusions: The blockade of oncoprotein Bcr-abl by imatinib could cause a decrease in the expression of key DNA repair genes, and cells try to restore the normal gene expression levels required for cell proliferation and chromosomal integrity.

2014-01-01 | GSE33075 | GEO

Physiologic Hypoxia Promotes Maintenance of CML Stem Cells Despite Effective BCR−ABL1 Inhibition

Project description:ABL1 kinase inhibitors such as imatinib mesylate (IM) are effective in managing chronic myelogenous leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinase−independent pathways support LSC survival. Given that the bone marrow hypoxic microenvironment supports hematopoietic stem cells, we investigated if hypoxia similarly contributes to LSC persistence. Importantly, we found that while BCR−ABL1 kinase remained effectively inhibited by IM under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of IM. HIF1−α, which is the master regulator of the hypoxia transcriptional response is expressed in the bone marrow specimens of CML individuals. In vitro, HIF1−α is stabilized during hypoxia and its expression and transcriptional activity can be partially attenuated by concurrent IM treatment. Expression analysis demonstrates at the whole transcriptome level that hypoxia and IM regulate distinct subsets of genes. Functionally, knockdown of HIF1−α abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1−α signaling supports LSC persistence independently of BCR−ABL1 kinase activity. Thus targeting HIF1−α and its pathway components may be therapeutically important for the complete eradication of LSCs.

2014-06-03 | GSE48294 | GEO

CENAT-AML-experiment1

Project description:Acute myeloid leukemia (AML) is the most common and severe acute leukemia in adults. It is a heterogeneous disease where the subset of molecularly different types, presenting various morphological features and differentiation stage, can be distinguished. Genomic research of leukemias is conducted since 1999 and large cohort studies shown that particular genetic alterations correspond with specific gene expression signatures. However, not always they provide clinically relevant information. The most unknown group is cytogenetically normal acute myeloid leukemia (CN-AML, 40-49% of all AML cases). The aim of our experiment was to determine selected gene expression profiles in CN-AML, using small, boutique microarray. The array contained 933 oligonucleotide probes, mainly complementary to acute myeloid leukemia markers, genes involved in leukemic transformation and myeloid cell proliferation, differentiation and maturation. Our test dataset included 40 hybridizations: 24 corresponding with blood and bone marrow samples collected from 12 patients with AML M1 or M2 FAB subtype and 16 corresponding with healthy control samples. Total RNA was extracted from the mononuclear cell fractions, reversibly transcribed to cDNA and labeled with Alexa 647 dye. The common reference was RNA isolated from HL-60 cell culture, labeled with Alexa 555 dye.

2013-07-01 | E-MEXP-3647 | biostudies-arrayexpress

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