Molecular reprogramming of granulocyte/macrophage progenitor (GMP) clusters upon induction of BCR/ABL oncogene
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE90797 | GEO | 2017/03/31
SECONDARY ACCESSION(S): PRJNA355981
REPOSITORIES: GEO
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Project description:Chronic myelogenous leukemia (CML) is a malignant disease of the hematopoietic stem cell, characterized by the expression of the Bcr-Abl oncogene by leukemic cells. In order to analyze the molecular pathways modulated by Bcr-Abl, we have previously generated an inducible model of Bcr-Abl expression in the murine Ba/F3 cell line based on the Tet-OFF system. In the present study, through a microarray approach applied to cells grown with (Bcr-Abl-expression OFF) or without (Bcr-Abl-expression ON) doxycycline, a tetracycline analogue, we analyzed the gene expression variations upon Bcr-Abl expression. Keywords: repeat sample
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Project description:Chronic myelogenous leukemia (CML) is a malignant disease of the hematopoietic stem cell, characterized by the expression of the Bcr-Abl oncogene by leukemic cells. In order to analyze the molecular pathways modulated by Bcr-Abl, we have previously generated an inducible model of Bcr-Abl expression in the murine Ba/F3 cell line based on the Tet-OFF system. In the present study, through a microarray approach applied to cells grown with (Bcr-Abl-expression OFF) or without (Bcr-Abl-expression ON) doxycycline, a tetracycline analogue, we analyzed the gene expression variations upon Bcr-Abl expression.
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Project description:Using a mouse model of chronic myelogenous leukemia (CML), here we report that HIF1α plays a crucial role in survival maintenance of leukemia stem cells (LSCs). Deletion of HIF1α impairs the propagation of CML through impairing cell cycle progression and inducing apoptosis of LSCs. Deletion of HIF1α results in elevated expression of p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1α-/- LSCs. To further identify the pathways in which Hif1a regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Hif1a-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+ cells, BCR-ABL-expressing wild type LSCs, and BCR-ABL-expressing Hif1a-/- LSCs.
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Project description:Using a mouse model of chronic myelogenous leukemia (CML), here we report that HIF1M-NM-1 plays a crucial role in survival maintenance of leukemia stem cells (LSCs). Deletion of HIF1M-NM-1 impairs the propagation of CML through impairing cell cycle progression and inducing apoptosis of LSCs. Deletion of HIF1M-NM-1 results in elevated expression of p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1M-NM-1-/- LSCs. To further identify the pathways in which Hif1a regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Hif1a-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+ cells, BCR-ABL-expressing wild type LSCs, and BCR-ABL-expressing Hif1a-/- LSCs. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without the Hif1a gene, we compared the gene profile between wild type (WT) LSCs and Hif1a-/- LSCs.
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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 β-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.
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Project description:Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for leukemia stem cells (LSCs), we showed that BCR-ABL down-regulates the B lymphoid kinase (Blk) gene in leukemia stem cells in CML mice and that Blk functions as a tumor suppressor in LSCs and suppresses LSC function. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. To identify the pathways in which Blk 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- and BCR-ABL-Blk expressing LSCs. This analysis revealed a large group of candidate genes that exhibited changes in the levels of transcription in the Blk expressing LSCs, and uncovered the molecular mechanisms by which Blk suppresses LSCs and CML development.
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Project description:The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p185, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p185 occurs in the majority of B-cell acute lymphoblastic leukemia. Differences in protein-protein interactions and activated signaling pathways that may be associated with the different diseases driven by p210 and p185 are unknown. We have performed a quantitative comparative proteomics study of p210 and p185 and found strong differences in the interactome and phosphoproteome. Whereas the AP2 endocytosis complex interacts preferentially with p185, the phosphatase Sts1 is enriched with p210. Stronger activation of STAT5 and ERK1/2 is observed with p210, whereas Lyn is activated by p185. These results were validated in human p210 and p185-positive cell lines. Our findings contribute to a more coherent understanding of Bcr-Abl signaling, mechanisms of oncogenic transformation, resulting disease pathobiology and responses to kinase inhibitors.
2017-01-31 | PXD005149 | Pride
Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity
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