Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse bcr-abl transformed cells reveals ICSBP-mediated immune protection against BCR-ABL-induced leukemia requires the CCL6 and CCL9 chemokines

ABSTRACT: Interferon is effective at inducing complete remissions in patients with Chronic Myelogenous Leukemia (CML), and evidence supports an immune mechanism. Here we show that the Type I Interferons (alpha and beta) regulate expression of the Interferon consensus sequence binding protein (ICSBP) in bcr-abl transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of bcr-abl induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the Type I Interferons and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the anti-leukemic response of interferons suggest new strategies for immunotherapy of CML. Experiment Overall Design: Total RNA was isolated from parental BaF3 cells as well as BaF3 cells expressing BCR-ABL, ICSBP, or both BCR-ABL and ICSBP. Using standard Affymetrix protocols the RNA samples were analyzed for gene expression using Affymetrix mouse 430_2 whole genome microarrays arrays. A threshold value of 50 was set for all genes and the list of genes filtered to include only those that had at least one Present flag ("P" flag) in one of the 4 conditions. For each gene, the ratio of its expression in a particular condition and its expression in parental BaF3 cells was determined. Only genes that had at least a 3-fold up or down change in expression were considered, leaving a set of 1431 genes for further analysis. K-means clustering with Gene cluster 3.0 was used to group these 1431 genes into 15 clusters and JavaTree was used to visualize the results.

ORGANISM(S): Mus musculus

SUBMITTER: George Daley

PROVIDER: E-GEOD-14416 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We previously demonstrated that Alox5 deficiency impairs the function of LSCs and prevents the initiation of BCR-ABL-induced CML. To identify the pathways in which Alox5 gene regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to further dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs derived from our mouse model for BCR-ABL-induced CML. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was up-regulated in Alox5-/- LSCs, suggesting that Msr1 might suppress the proliferation of LSCs. Using our CML mouse model, we show that Msr1 is down-regulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and ?-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of Msr1 function may be of significance in the development of novel therapeutic strategies targeting CML. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without Alox5 gene, we compared the gene profile between wild type(WT) LSCs or Alox5-/- LSCs.

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Transcription profiling of mouse bcr-abl transformed cells reveals ICSBP-mediated immune protection against BCR-ABL-induced leukemia requires the CCL6 and CCL9 chemokines

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