Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-20987
PROVIDER: PRJNA132615 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we used genome tiling arrays to identify BCL6 target genes with specific recruitment of BCL6.
2011-02-15 | GSE24404 | GEO
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we used genome tiling arrays to identify BCL6 target genes with specific recruitment of BCL6. Three Ph+ ALL cell lines (BV-173, NALM-1 and TOM-1) in duplicate were either treated with 10µM STI571 (Imatinib) for 24 hours or cultured in absence of STI571.
2011-02-15 | E-GEOD-24404 | biostudies-arrayexpress
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI.
2011-03-01 | GSE24381 | GEO
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI. Three Ph+ ALL cell lines (BV-173, SUP-B15 and TOM-1) were treated in the presence or absence of 10 μM STI571 (Imatinib) or in the presence of both 10 μM STI571 and 20 μM RI-BPI for 24 hours.
2011-03-01 | E-GEOD-24381 | biostudies-arrayexpress
Project description:We identified the BCL6 protooncogene as a critical downstream effector of FoxO3A in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for leukemia stem cell maintenance, colony formation and initiation of leukemia in transplant recipients. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in xenotransplanted mouse recipients. These findings identify peptide-inhibition of BCL6 as a novel strategy to eradicate leukemia-initiating cells in CML. Identification of BCL6 binding sites in human CML cell line JURL-MK1
2011-09-15 | E-GEOD-26085 | biostudies-arrayexpress
Project description:We identified the BCL6 protooncogene as a critical downstream effector of FoxO3A in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for leukemia stem cell maintenance, colony formation and initiation of leukemia in transplant recipients. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in xenotransplanted mouse recipients. These findings identify peptide-inhibition of BCL6 as a novel strategy to eradicate leukemia-initiating cells in CML.
2011-09-15 | GSE26085 | GEO
Project description:Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 myeloid progenitor cell lines transduced with an empty vector or oncogenic mutant KIT (V560G, D816V). Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK at threonine 2599 in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling via using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Discovery phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib single-agent treatment inhibited ERK1 activity, and M3814 single-agent treatment inhibited Akt/mTOR activity. The combination of dasatinib and M3814 treatment inhibited both ERK/MAPK and Akt/mTOR activity, and induced synergistic inhibition of phosphorylation of transcription regulators including MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising novel therapeutic target for KIT mutant cancers.
2023-01-26 | PXD030214 | panorama
Project description:Fusions involving tyrosine kinases are oncogenic drivers in lung cancer and other solid tumors but also mediate resistance to targeted therapy. Despite gene rearrangements involving tyrosine kinases tending to show recurrent patterns in solid tumors, little is known about their mechanisms of formation and their selection process. To elucidate these mechanisms, we developed a functional high-throughput, genome-wide translocation sequencing (F-HTGTS) approach. We applied F-HTGTS to lung cancer cells under the selective pressure of EGFR inhibition to map genome-wide translocations when a DNA double-strand break occurs in the ALK, RET, ROS1 or NTRK1 tyrosine kinase. We found that translocations form spontaneously with several partners in the genome, generate functional fusion proteins and induce resistance to EGFR inhibitors. Several of these proteins reproduce precisely the fusions found in NSCLC patients either as original driver events or secondary to development of resistance to targeted therapy. Therefore, F-HTGTS is an approach that allows rapid and comprehensive mapping of tyrosine kinase fusions in the genome from common oncogenic kinases and provide insights on their mechanisms of formation.
2024-04-29 | GSE167155 | GEO
Project description:BCL6 is a transcription repressor that plays a crucial role in germinal center formation and lymphomagenesis. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). Heterogeneous levels of BCL6 were found across AML cell lines and primary AML samples. Cells with higher levels of BCL6 were indeed sensitive to treatment with BCL6 inhibitors. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed a subset of target genes that are common with lymphoma cells. Ex vivo treatment of primary AML cells with BCL6 peptide inhibitor (BPI) induced apoptosis and decrease colony forming capacity which correlated with the levels of BCL6 expression . Importantly, inhibition of BCL6 in primary AML cells with either BPI or BCL6 siRNA resulted in significant reduction of leukemia initiating capacity using immunodeficient mice, suggesting ablation of leukemia stem cells (LSC). Such anti-LSC activity was also observed as downregulation of LSC gene signatures using gene expression analyses of cells treated with a BCL6 inhibitor. Importantly, treatment with cytarabine (AraC) induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML primary derived xenografts (PDX) revealed that when AraC was combined with BCL6 inhibitor, inhibition of BCL6 significantly potentiated the efficacy of AraC and improved cytotoxic effects by interfering with the leukemia initiating capacity of AML cells. This suggests that pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of LSCs and overcome chemoresistance in AML.
2020-08-01 | GSE133112 | GEO
Project description:Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) are developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of Pol II. The resulting BCL6-target proapoptotic gene expression translates into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72h with EC50s of 0.9 – 10nM and specific ablation of the BCL6-dependent germinal center response in mice. The molecules exhibit 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborate a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.
2024-09-18 | GSE245598 | GEO