Gene expression profiling in BCR-ABL expressing LSCs and BCR-ABL-BLK expressing LSCs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE36096 | GEO | 2012/07/06
SECONDARY ACCESSION(S): PRJNA151801
REPOSITORIES: GEO
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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. Bone marrow cells were transduced with GFP, BCR-ABL-GFP or BCR-ABL-Blk-GFP, followed by transplantation into recipient mice. Fourteen days after transplantation, bone marrow cells were isolated and LSCs were sorted by FACS for isolation of total RNA for DNA microarray analysis.
2012-07-05 | E-GEOD-36096 | biostudies-arrayexpress
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.
2011-05-17 | E-GEOD-29347 | biostudies-arrayexpress
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.
2012-04-03 | E-GEOD-35111 | biostudies-arrayexpress
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.
2012-04-04 | GSE35111 | GEO
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.
2011-05-17 | GSE29347 | GEO
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
2005-05-01 | GSE1429 | GEO
Project description:The BCR-ABL oncogene, generated by Philadelphia chromosome, is present in about 95% human Chronic myeloid leukemia (CML) and 20~30% acute lymphoblastic leukemia (ALL). One of BCR-ABL isoforms, P210, is more often detected in CML and ALL patients. Although BCR-ABL kinase inhibitors are effective in controlling the diseases, they do not provide cure due to the development of drug resistance and the insensitivity of leukemia stem cells to these drugs. Identification of new therapeutic targets is critical. To identify potential target against leukemia stem cells, we studied gene expression in leukemia stem cells, which were identified in mice in our lab (Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. 2006. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia. Proc Natl Acad Sci USA 103(45):16870-16875.). The sorted leukemia stem cells that expressed BCR-ABL were used for isolation of RNA, followed by the analysis of gene expression using the DNA microarray. The same lineage of non-BCR-ABL-expressing normal hematopoietic stem cells was used as control. We have identified some interesting genes that are up- or down-regulated by BCR-ABL in these leukemia stem cells. We are currently studying the functions of these identified genes. Keywords: Genetic modification
2008-03-22 | GSE10912 | GEO
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.
2005-05-01 | E-GEOD-1429 | biostudies-arrayexpress
Project description:Aberrant long noncoding RNA (lncRNA) expression has been described in many human malignancies, including leukemia. Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a stem cell disease induced by Bcr-Abl hybrid gene. Here we attempt to identify lncRNAs associated with CML by analyzing lncRNA expression profiles in K562 cells when Bcr-Abl gene silenced. LncRNA microarray analysis revealed a group of lncRNAs that exhibit Bcr-Abl-dependent expression. In this study, we focused on lncRNA-X that was downregulated by Bcr-Abl, suggesting that lncRNA-X might have a function of tumor suppression. We showed that lncRNA-X over-expression delays Bcr-Abl-induced tumorigenesis in vivo, maybe through its effect on cell survival by modulating STAT5-dependent expression of anti-apoptotic Bcl-XL protein. We also demonstrated that lncRNA-X may affect tumor formation behavior of Bcr-Abl-transformed cells by regulating signaling pathways associated with leukemia stem cells of CML. Together, these results suggest that lncRNA-X suppresses Bcr-Abl-induced tumorigenesis, and the tumor suppressor function of lncRNA-X may be of significance for exploring novel therapeutic strategies for treating CML. This microarray was performed to identify lncRNAs associated with Bcr-Abl-induced chronic myeloid leukemia (CML).
2015-07-20 | GSE42269 | GEO
Project description:Background In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure. Methods In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments. Results Here, we present compelling evidence elucidating the sensitivity of DSF, an FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's ability to circumvent resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting GPX4 ubiquitination and subsequent degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models. Conclusion In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.
2024-09-05 | GSE276122 | GEO