Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA246571 | ENA |
REPOSITORIES: ENA
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Project description:Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) can be subdivided into different categories based on genetic abnormalities. One type of pre-B ALL is characterized by the presence of the Philadelphia (Ph) chromosome, the derivative chromosome 22 that is one product of a reciprocal translocation between chromosomes 22 and 9. The 22/9 translocation fuses the 5’ part of the BCR gene to the 3’ end of the c-ABL gene. The resulting BCR/ABL fusion encodes a Bcr/Abl protein with deregulated Abl kinase activity. Two major fusion proteins are found in Ph-positive leukemias which differ in molecular weight and the size of the Bcr moiety. The P190 Bcr/Abl protein is common in Ph-positive ALL. Targeted tyrosine kinase inhibitors such as nilotinib are used therapeutically to treat this type of leukemia. The 22/9 translocation fuses the 5’ part of the BCR gene to the 3’ end of the c-ABL gene. The resulting BCR/ABL fusion encodes a Bcr/Abl protein with deregulated Abl kinase activity. Two major fusion proteins are found in Ph-positive leukemias which differ in molecular weight and the size of the Bcr moiety. The P190 Bcr/Abl protein is common in Ph-positive ALL. Targeted tyrosine kinase inhibitors such as nilotinib are used therapeutically to treat this type of leukemia.
2018-02-05 | GSE110104 | GEO
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:BCR-ABL positive acute lymphoblastic leukemia (ALL) cell survival is strongly dependent on the IRE1α-XBP1 branch of the Unfolded Protein Response (UPR). In the study at hand, we have focused on exploring the link between BCR-ABL1 and IRE1α to better understand whether a simultaneous pharmacological inhibition of both pathways could represent a beneficial therapeutic strategy in Philadelphia positive (Ph+) ALL. Therefore, the effect on the phosphoproteome of two inhibitors (MKC-8866 and Nilotinib) as well as a combination of both compounds was analysed in this study.
2020-09-21 | PXD012024 | Pride
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: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:Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia
| PRJNA633578 | ENA
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. Experiment Overall Design: Identification of genes that are regulated by BCR/ABL in HSCs. Experiment Overall Design: Bone marrow cells are isolated from the long bones of CML mice that are untreated or treated with imatinib. BCR-ABL-expressing or non-BCR-ABL-expressing (transduced with the empty GFP vector) hematopoietic stem cells (GFP+Lin-c-Kit+Sca-1+) are stored by FACS directly into RNAlater (Ambion, Austin, TX) and are homogenized in RLT Buffer (RNeasy Micro Kit (Qiagen, Valencia, CA)). Total RNA is isolated by following the protocol for the RNeasy Micro Kit, and quality is assessed using a 2100 Bioanalyzer instrument and RNA 6000 Pico LabChip assay (Agilent Technologies, Palo Alto, CA). Utilizing the GeneChip Whole Transcript Sense Target Labeling Assay kit (Affymetrix, Santa Clara, CA.) between 100-300ng of total RNA undergoes reverse transcription with random hexamers tagged with T7 sequence. The double stranded cDNA that is generated is then amplified by T7 RNA polymerase to produce cRNA. Second cycle first strand cDNA synthesis then takes place incorporating dUTP which is later used as sites where fragmentation occurs by utilizing an uracil DNA glycosylase and apurinic/apyrimidinic endonuclease 1 enzyme mix. The fragmented cDNA is then labeled by terminal transferase attaching a biotin molecule using Affymetrix proprietary DNA labeling Reagent. Approximately 2.0µg of fragmented and biotin-labeled cDNA is then hybridized onto a Mouse Gene ST 1.0 Array (Affymetrix, Santa Clara, CA.) for 16 hours at 45°C. Post-hybridization staining and washing are performed according to manufacturer's protocols using the Fluidics Station 450 instrument (Affymetrix). Finally, the arrays are scanned with a GeneChip? Scanner 3000. Images are acquired and cel files generated which are then used for analysis.
2008-04-04 | E-GEOD-10912 | biostudies-arrayexpress
Project description:Philadelphia chromosome-positive B-cell acute lymphoblastic leukaemia (Ph+B-ALL), characterised by the BCR-ABL1 fusion gene, remains a poor prognosis cancer that needs new therapeutic approaches. Transcriptomic profiling and pathway analysis identified up-regulation of the oncogenic transcription factors ERG and c-MYC, with enrichment of genes involved in metabolic processes including ribosome biogenesis.
2024-01-25 | GSE213791 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24381: Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia GSE24404: Recruitment of BCL6 to target genes in Philadelphia chromosome positive acute lymphoblastic leukemia Refer to individual Series
2011-02-15 | E-GEOD-24426 | biostudies-arrayexpress
Project description:Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to completely eradicate Bcr-Abl+ leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl+ leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib in CML cells. This screen identified numerous components of a Wnt/Ca2+/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl+ acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl+ leukemias.
2010-07-15 | GSE21499 | GEO