Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA150179 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from point mutations or chimaeric fusion genes, such as BCR ABL1 or JAK2 V617F. We report here for the first time in hematological malignancies, two novel fusion genes involving the TK RET, BCR-RET and FGFR1OP-RET, in chronic myelo monocytic leukemia (CMML) cases. The two RET fusion genes lead to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. We also report that the BCR-RET fusion protein is insensitive to Imatinib but sensitive to Sorafenib in vivo. CMML is an hematopoietic malignancy associated with the frequent activation of the RAS pathway. The RET fusion genes seems to constitutively mimic the same signaling pathway than RAS mutations. Overall, the RET fusion genes behaviors in the monocytic lineage underlie the role of the normal RET TK activity during the physiological monocytic differentiation. We analysed BAF/3 cells infected by BCR-RET, FGFR1OP-RET or BCR-ABL1P210 fusion genes retroviruses and sorted out using EGFP fluorescence, with Affymetrix GeneChip MouseGene 1.0 ST platform.
2012-01-06 | E-GEOD-34900 | biostudies-arrayexpress
Project description:Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from point mutations or chimaeric fusion genes, such as BCR ABL1 or JAK2 V617F. We report here for the first time in hematological malignancies, two novel fusion genes involving the TK RET, BCR-RET and FGFR1OP-RET, in chronic myelo monocytic leukemia (CMML) cases. The two RET fusion genes lead to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. We also report that the BCR-RET fusion protein is insensitive to Imatinib but sensitive to Sorafenib in vivo. CMML is an hematopoietic malignancy associated with the frequent activation of the RAS pathway. The RET fusion genes seems to constitutively mimic the same signaling pathway than RAS mutations. Overall, the RET fusion genes behaviors in the monocytic lineage underlie the role of the normal RET TK activity during the physiological monocytic differentiation.
2012-01-06 | GSE34900 | GEO
Project description:Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, application of FLT3 small molecule inhibitors such as Sorafenib has resulted only in partial and transient clinical responses in FLT3-ITD+ patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with Sorafenib in addition to standard therapy. Here, we studied the Sorafenib effect on proliferation in a panel of 13 FLT3-ITD- and FLT3-ITD+ AML cell lines. Sorafenib IC50 values ranged from 0.001 to 5.6 µM, whereas FLT3-ITD+ cells (MOLM-13, MV4;11) were found more sensitive to Sorafenib than FLT3-ITD- cells. However, we identified two FLT3-ITD- cell lines (MONO-MAC-1 and OCI-AML-2) which were also Sorafenib sensitive. Phosphoproteome analyses revealed that the affected pathways differed in Sorafenib sensitive FLT3-ITD- and FLT3-ITD+ cells. In MV4;11 cells Sorafenib suppressed mTOR signalling by inhibiting direct inhibition of FLT3. In MONO-MAC-1 cells Sorafenib inhibited the MEK/ERK pathway by inhibition of the RET tyrosine kinase. These data suggest that the FLT3 status in AML patients might not be the only predictive factor for a response to Sorafenib.
2017-05-02 | PXD004442 | Pride
Project description:To identify gene expression changes associated with receptor tyrosine kinase (RTK) activation, we performed RNA-Seq analysis of murine pro-B BAF3 cells over-expressing the oncogenic form of EGFR (EGFR-L858R-T790M), FGFR (TEL-FGFR1 fusion), MET (TPR-MET fusion) or RET (CCDC6-RET fusion) genes. We reported the RTK-driven transcriptional reprogramming of metabolic genes.
2020-04-10 | GSE111292 | GEO
Project description:Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5-10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that the cellular expression of the kinase fusions leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1 and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
2021-04-27 | PXD021904 | Pride
Project description:The 8p11 myeloproliferative syndrome (EMS), also referred to as the stem cell leukemia/lymphoma syndrome, is a chronic myeloproliferative disorder that rapidly progresses into an acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinase activity within FGFR1. The two most common fusion genes in human EMS are ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) and BCR/FGFR1. To study the transcriptional programs becoming deregulated by the FGFR1 fusion genes, global gene expression analysis on human CD34+ cord blood cells expressing either of the fusion oncogenes ZMYM2/FGFR1 and BCR/FGFR1 was performed. As a reference gene we also included the more studied BCR/ABL1 fusion oncogene associated with chronic myeloid leukemia. We found that the 3 different fusion oncogenes had in common the upregulation of several genes involved in the JAK/STAT signalling pathway and also other sets of genes. However, the gene expression profiles were not identical, suggesting that both the tyrosine kinase containing gene and the partner gene would affect the transcription of downstream target genes. Bicistronic retroviral murine stem cell virus (MSCV) vectors expressing ZMYM2/FGFR1, BCR/FGFR1or P210 BCR/ABL1 and GFP were used. The MIG control vector expressed GFP only. Two days post transfection of human CD34+ umbilical cord blood cells, GFP-sorted cells were collected in three biological replicates and RNA was isolated immediately. In total, 12 samples were hybridized and scanned.
2010-05-27 | E-GEOD-15811 | biostudies-arrayexpress
Project description:Transcriptionally active ESR1 fusions promote endocrine therapy (ET)-resistant growth and metastasis of estrogen receptor-alpha positive (ERα+) breast cancer. Currently, there are no targeted treatment options for tumors harboring active fusions because the ESR1 ligand binding domain (LBD) has been replaced with non-drug binding sequences from the 3’ partner gene. A mass spectrometry (MS)-based Kinase Inhibitor Pulldown Assay (KIPA) demonstrated an increase of multiple receptor tyrosine kinases including RET in T47D cells expressing active ESR1 fusions. Integrated proteogenomics defined tumor subsets that could be responsive to RET and CDK4/6 directed therapy from 22 biologically heterogeneous ERα+ patient-derived xenograft (PDX) tumors. Inhibition of RET by repurposing an FDA-approved drug significantly suppressed ESR1 fusion-driven growth of cell, PDX-derived organoid (PDXO) and PDX models. CDK4/6 inhibitor treatment showed similar tumor reductions to RET inhibition. Here, we reveal therapeutic kinase vulnerabilities in ESR1 fusion-driven tumors, which will lay the framework for future clinical trials.
2023-10-24 | PXD033339 | Pride
Project description:Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. From a set of PTC patients whose tumor did not harbour any BRAF or RAS mutations, a 35 years old male patient’s normal, primary tumor and lymph node (LN) metastatic tissues were subjected to genomics and proteomics analysis. By RNA-seq analysis, we identified a novel RET rearrangement involving exons 1-4 from the 5’ end of the Trk fused Gene (TFG) fused to the 3’ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. Further, TFG-RET oncogene oligomerises in a PB1 domain-dependent manner and consistently, mutation of the oligomerisation interface led to the inhibition of RET-mediated oncogenic transformation. Quantitative proteomic analysis of the same samples revealed the upregulation of proteins involved in the ubiquitination machinery including E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and LN metastatic lesions. We further identified that expression of TFG-RET led to the upregulation of HUWE1. Further, in a cohort of PTC patients, we observed higher expression of HUWE1, USP9X and USP7 in the tumor and metastatic lesions, when compared to the matched normal tissue. Transient knockdown of HUWE1, USP9X and USP7 affected viability and proliferation of TFG-RET transformed cells. Consistently, inhibition of RET, HUWE1 and DUBs by small molecule inhibitors significantly reduced RET-mediated oncogenesis. Apart from unveiling a novel oncogenic RET fusion in PTCs, our data may open a novel avenue of targeting ubiquitin signaling machinery in human PTCs.
2020-04-02 | PXD016828 | Pride
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:Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. From a set of PTC patients whose tumor did not harbour any BRAF or RAS mutations, a 35 years old male patient’s normal, primary tumor and lymph node (LN) metastatic tissues was subjected to genomics and proteomics analysis. By RNA-seq analysis, we identified a novel RET rearrangement involving exons 1-4 from the 5’ end of the Trk fused Gene (TFG) fused to the 3’ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase dependent manner. Further, TFG-RET oncogene oligomerises in a PB1 domain dependent manner and consistently, mutation of the oligomerisation interface led to the inhibition of RET-mediated oncogenic transformation. Quantitative proteomic analysis of the same samples revealed the upregulation of proteins involved in the ubiquitination machinery including HECT carrying E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in the tumor and LN metastatic lesions. We further identify that expression of TFG-RET led to the upregulation of HUWE1. Further, in a cohort of PTC patients, we observed higher expression of HUWE1, USP9X and USP7 in the tumor and metastatic lesions, when compared to the matched normal tissue. Transient knockdown of HUWE1, USP9X and USP7 affected viability and proliferation of TFG-RET transformed cells. Consistently, inhibition of RET, HUWE1 and DUBs by small molecule inhibitors significantly reduced RET-mediated oncogenesis. Apart from unveiling a novel oncogenic RET fusion in PTCs, our data may open a novel avenue of targeting ubiquitin signaling machinery in human PTCs.
2020-04-02 | PXD016739 | Pride