Imatinib effects on CD34+ cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE1418 | GEO | 2004/05/24
SECONDARY ACCESSION(S): PRJNA90017
REPOSITORIES: GEO
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Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound ≥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells.
2008-07-30 | GSE12211 | GEO
Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound â¥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells. Experiment Overall Design: In total 6 patients with new diagnosis CML (Chronic Myelogenous Leukemia) in chronic phase are inculded in the study. The gene expression profiles of the CD34+ hematopoietic stem and progenitor cells from the patients before first treatment with Glivec (Imatinib) are compared to the gene expression profiles of the CD34+ hematopoietic stem and progenitor cells of the same patients after 7 days of treatment with 400 mg Glivec / day.
2008-10-21 | E-GEOD-12211 | biostudies-arrayexpress
Project description:purified CD34+ cells from bone marrow of imatinib-treated patients were compared to those of healthy donors
2007-07-29 | E-GEOD-1418 | biostudies-arrayexpress
Project description:Imatinib, as the first-line agent of chronic myeloid leukemia (CML), is ineffective in eradicating CML stem/progenitor cells, thus unable to prevent late relapse. Here we present data indicating that fenretinide preferentially targets CD34+ CML cells and enhances the efficacy of imatinib in CML. As tested by colony forming cell assays, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and those derived from more primitive pluripotent progenitor cells were highly sensitive to fenretinide/fenretinide plus immtinib. Further data showed that fenretinide was able to induce apoptosis in CD34+ CML cells which were refractory to imatinib. Through transcriptome analysis and followed by molecular validation, we further showed that apoptosis induced by fenretinide in CD34+ CML cells was mediated by complex mechanisms of stress responses, probably triggered by elevated levels of intracellular reactive oxygen species. Thus, fenretinide combines with imatinib may represent a new strategy for the treatment of CML, in which fenretinide targets primitive CD34+ CML cells whereas imatinib targets leukemic blasts. This strategy may eventually reduce the risk of relapse and probably resistant as well in CML patients.
2009-12-01 | GSE17480 | GEO
Project description:In our previous study, the roles of zinc finger protein X-linked (ZFX) in CML cells were revealed. We showed that ZFX expression was significantly higher in CML CD34+ cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. To obtain molecular insights of how ZFX modulates the growth and imatinib response of CML stem and progenitor cells, we generated microarray data comparing ZFX silenced CML CD34+ cells with control (Scramble) cells.
2023-11-13 | GSE241116 | GEO
Project description:Imatinib therapy is first-line treatment for chronic myeloid leukemia (CML), and its failure to target CML progenitor/stem cells may lead to an increased risk of relapse. We report here that fenretinide, a well-tolerated vitamin A derivative, is capable of eradicating primitive CML progenitor/stem cells and significantly enhances the efficacy of imatinib at physiologically achievable concentrations. As tested by colony forming cell assays, formation of various colonies derived primitive CML CD34+ cells was significantly suppressed by fenretinide, particularly with respect to the formation of colonies derived from erythroid progenitors and more primitive CML progenitor/stem cells. Also, fenretinide significantly enhanced the ability of imatinib to suppress the formation of the colonies. Moreover, fenretinide was able to induce apoptosis in primitive CML CD34+ cells while sparing the normal counterparts. In particular, primitive CML CD34+CD38- cells appeared to be most sensitive to fenretinide induced apoptosis. Through transcriptome analysis and molecular validation, we further showed that fenretinide induced apoptosis in CML CD34+ cells was probably mediated by a series of stress responsive events which were likely triggered by elevated levels of intracellular reactive oxygen species. Accordingly, the combination of fenretinide and imatinib may provide a potential solution for overcoming relapse and resistance in CML. Experiment Overall Design: Transcriptome profiles of CML CD34+ cells with and without fenretinide treatment were analyzed using whole genome expression arrays (Affymetrix HG-U133 Plus 2.0) in four CML patients (CML32, CML33, CML34 and CML35, see Table 1). To minimize potential data biases, both treated and untreated cell samples were maintained in culture for 48 hours before hybridization.
2009-12-05 | E-GEOD-17480 | biostudies-arrayexpress
Project description:Integrated Stress Response (ISR) facilitates cellular adaptation to a variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CML-BP CD34+ resistant cells. We found that In PDX mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFN pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.
2022-11-04 | GSE171853 | GEO
Project description:This is a class prediction experiment, where the class is the response status to imatinib (also called Gleevec), a drug used to treat patients with chronic myelogenous leukemia (CML). There are two data sets, a training set (from Leipzig, 8 Responders and 5 Non-Responders) and a validation set (from Mannheim, 8 Responders and 7 Non-Responders). The objective is to identify differentially regulated genes between CML patients who respond and those who do not respond to imatinib and confirm the results in the validation data set. The samples from blood or bone marrow of CML patients were hybridized to Affymetrix HG-U95Av2 chip and RMA was used to generate the normalized signal values. Keywords = chronic myelogenous leukemia Keywords = imatinib Keywords = cytogenetic responses Keywords = Gleevec Keywords = Affymetrix Keywords: other
2005-04-18 | GSE2535 | GEO
Project description:To ascertain genomic alterations associated with Imatinib resistance in chronic myeloid leukaemia, we performed high resolution genomic analysis of CD34+ cells from 25 Imatinib (IM) resistant and 11 responders CML patients. Using patients' T-cells as reference, we found significant association between number of acquired cryptic copy number alterations (CNA) and disease phase (p=0.036) or loss of IM response for patients diagnosed in chronic phase (CP) (p=0.04). Recurrent cryptic losses were identified on chromosomes 7, 12 and 13. On chromosome 7, recurrent deletions of the IKZF1 locus were detected, for the first time, in four patients in CP. Patients suffering from chronic myeloid leukaemia were compared using CD34+ cells and T cells as reference and hybridized on Agilent-014698 Whole Human Genome 105K microarrays.
2010-11-15 | E-GEOD-21986 | biostudies-arrayexpress
Project description:To ascertain genomic alterations associated with Imatinib resistance in chronic myeloid leukaemia, we performed high resolution genomic analysis of CD34+ cells from 25 Imatinib (IM) resistant and 11 responders CML patients. Using patients' T-cells as reference, we found significant association between number of acquired cryptic copy number alterations (CNA) and disease phase (p=0.036) or loss of IM response for patients diagnosed in chronic phase (CP) (p=0.04). Recurrent cryptic losses were identified on chromosomes 7, 12 and 13. On chromosome 7, recurrent deletions of the IKZF1 locus were detected, for the first time, in four patients in CP.
2010-11-15 | GSE21986 | GEO