Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human untreated and fenretinide-treated CD34+ cells from 4 CML patients

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Hai Fang

PROVIDER: E-GEOD-17480 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSC from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSC) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony forming ability and engraftment potential in immunodeficient mice. We found that the N-Cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-Cadherin-mediated adhesion to MSC was associated with increased cytoplasmic N-Cadherin-M-NM-2-catenin complex formation, as well as enhanced M-NM-2-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated M-NM-2-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-Cadherin and the Wnt-M-NM-2-catenin pathway in protecting CML LSC during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSC to TKI treatment, and suggest new targets for treatment designed to eradicate residual LSC in CML patients. RNA was obtained from CML CD34+ cells treated with or without IM (5M-NM-<M) and MSC for 96 hours, amplified, labeled and hybridized to GeneChip 1.0 arrays (Affymetrix, Santa Clara, CA). Microarray data analysis was performed using R (version 2.9) with genomic analysis packages from Bioconductor (version 2.4). The 33297 probes represented on the microarray were filtered by cross-sample mean, and for standard deviation of greater than the 25% quantile, yielding 18624 probes representing 12553 genes. Linear regression was used to model the gene expression with the consideration of a 2x2 factorial design and matched samples. Differentially expressed genes were identified by calculating empirical Bayes moderated t-statistic, and p-values were adjusted by FDR using the M-bM-^@M-^\LIMMAM-bM-^@M-^] package. Gene Set Enrichment Analysis (GSEA) was performed using GSEA software version 2.04 to detect enrichment of predetermined gene sets using t-scores from all genes for 1263 gene sets in the C2 (curated gene sets) category from the Molecular Signature Database (MsigDB).

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Transcription profiling of human untreated and fenretinide-treated CD34+ cells from 4 CML patients

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