Expression profile of Imatinib treated BAF3 -BCR-ABL cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75056 | GEO | 2017/03/20
SECONDARY ACCESSION(S): PRJNA302300
REPOSITORIES: GEO
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Project description:The Baf3 are dependent on IL-3 for grwoth however transformation by BCR -ABL oncogene causes BAf3 cells independent of IL-3. The BAf3 cells expressing BCR-ABL are dependent on continuous expression of BCR_ABL for growth. Inhibitionof BCR-ABL by its inhibitor Imatinib cause these cells to undergo apoptosis. When these cells are grown with IL-3 these cells do not respond to Imatinib mediated grwoth arrest.
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Project description:One of the main objective of this study is to characterize Imatinib induced MSCs-mediated resistance evolution in BCR-ABL+ ALL. Tyrosine kinase inhibitor (TKI) Imatinib (IM) is used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to IM therapy develops rapidly in a substantial proportion of treated patients, and the molecular mechanisms underlying the resistance are poorly understood. In this study, we identified a novel cascade of consequential events that are initiated by IM, which traverse through mesenchymal stem/stromal cells (MSCs) to leukemic cells, and lead to IM resistance. Our data showed that MSCs exposed to IM were decreased in their stemness and acquired a new functional status that enabled the formation of leukemic cell niches. These MSCs had increased expression of genes encoding chemo-attractants, adhesion molecules, and pro-survival stimulant growth factors. We found that BCR-ABL+ leukemic cells persistently exposed to IM were able to switch from BCR-ABL–driven signaling to growth factor–driven signaling for survival, and this switch was reversible. Blocking both the BCR-ABL–driven pathway and the growth factor–driven JAK pathway effectively eradicated the leukemic cell niches. Our findings illustrate TKI-induced, MSC-mediated drug resistance, suggesting an effective way to eliminate this type of drug resistance in patients with BCR-ABL+ ALL. Gene expression signatures were compared from triplicate samples of MSCs that were either treated with vehicle or imatinib for 32, 64 and 96 hours.
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Project description:One of the main objective of this study is to characterize Imatinib induced MSCs-mediated resistance evolution in BCR-ABL+ ALL. Tyrosine kinase inhibitor (TKI) Imatinib (IM) is used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to IM therapy develops rapidly in a substantial proportion of treated patients, and the molecular mechanisms underlying the resistance are poorly understood. In this study, we identified a novel cascade of consequential events that are initiated by IM, which traverse through mesenchymal stem/stromal cells (MSCs) to leukemic cells, and lead to IM resistance. Our data showed that MSCs exposed to IM were decreased in their stemness and acquired a new functional status that enabled the formation of leukemic cell niches. These MSCs had increased expression of genes encoding chemo-attractants, adhesion molecules, and pro-survival stimulant growth factors. We found that BCR-ABL+ leukemic cells persistently exposed to IM were able to switch from BCR-ABL–driven signaling to growth factor–driven signaling for survival, and this switch was reversible. Blocking both the BCR-ABL–driven pathway and the growth factor–driven JAK pathway effectively eradicated the leukemic cell niches. Our findings illustrate TKI-induced, MSC-mediated drug resistance, suggesting an effective way to eliminate this type of drug resistance in patients with BCR-ABL+ ALL.
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Project description: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.
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