DETECTION OF FOUR NOVEL RENAL TUMORS CASES HARBORING RBM10-TFE3 FUSIONS
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ABSTRACT:
PROVIDER: PRJNA674304 | ENA |
REPOSITORIES: ENA
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Project description:Microphtalmia-associated-transcriptional-factor-family translocation renal cell carcinoma (MiTF-tRCC) currently includes two main subtypes: “TFEB-tRCC” most often characterized by a t(6;11)(p21;q13) that generates a fusion of TFEB with MALAT1 and “TFE3-tRCC” characterized by rearrangements of TFE3 at Xp11.23 (2-3) that produce a variety of fusion genes. FISH is a handy method in routine practice that allows the detection of a rearrangement of TFE3. However, it reaches its limits in cases of micro-inversions or insertions: in fact paracentric microinversions that involve GRIPAP1 (Xp11.23) (23, Classe) or RBM10 (Xp11.3), very close to TFE3 , are most often undetectable.We report the clinical, immunohistological, genomic and molecular description of four novel TFE3-tRCC with RBM10-TFE3 fusion detected by targeted RNASeq analysis that illustrate the difficulties of diagnosis, especially in reason of disconcerting negative TFE3 FISH results.
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Project description:TFE3 is a member of the basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS) we interrogated a number of oncogenic mechanisms of TFE3-SF-containing fusions. We demonstrate that inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. Using HTHCS combined with FRET technology, we screened the FDA approved drugs library LOPAC and a small molecule library (Microsource) and identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D models utilizing patient derived xenolines and xenografts expressing TFE3-SF. The antihistamine terfenadine demonstrated decreased cell proliferation and reduced in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.
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Project description:Genome-wide CRISPR-Cas9 knockout screen using TKOv1 sgRNA library was performed in isogenic RBM10-proficient and RBM10-deficient HCC827 cells.
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Project description:The bHLH transcription factor Tfe3 is a powerful regulator of pluripotency and we report a genome-wide analysis of Tfe3 occupancy in mouse ES cells. Nuclear localization of Tfe3 is inhibited by a protein complex containing the tumor-suppressor Folliculin (Flcn) and we also determine Tfe3 binding sites in ES cells expressing an shRNA targeting Flcn. Specificity is controlled for by using unspecific IgGs and ES cells expressing an shRNA targeting Tfe3. ChIP-Seq profiling of Tfe3 in ES cells
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Project description:RBM10 is an RNA binding protein that was identified as a component of spliceosome complex, suggesting its potential role in splicing regulation. However, the direct experimental evidence for this function has been lacking. Here we characterized in vivo RBM10-RNA interactions and investigated the role of RBM10 in splicing regulation at the global level. We observed significant RBM10-RNA interactions in the vicinity of splice sites and identified hundreds of splicing changes following perturbation of cellular RBM10 abundance. A RNA splicing map integrating the binding pattern and splicing profiles revealed a significant correlation between RBM10-enhanced exon skipping events and its binding close to the splicing sites of both upstream and downstream introns. Furthermore, we demonstrated the splicing defects in a patient carrying a RBM10 mutation. Overall, our data provided insights into the mechanistic model of RBM10-mediated splicing regulation and established genomic resources for future studies on its function in different pathophysiological contexts.
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Project description:RBM10 is an RNA binding protein that was identified as a component of spliceosome complex, suggesting its potential role in splicing regulation. However, the direct experimental evidence for this function has been lacking. Here we characterized in vivo RBM10-RNA interactions and investigated the role of RBM10 in splicing regulation at the global level. We observed significant RBM10-RNA interactions in the vicinity of splice sites and identified hundreds of splicing changes following perturbation of cellular RBM10 abundance. A RNA splicing map integrating the binding pattern and splicing profiles revealed a significant correlation between RBM10-enhanced exon skipping events and its binding close to the splicing sites of both upstream and downstream introns. Furthermore, we demonstrated the splicing defects in a patient carrying a RBM10 mutation. Overall, our data provided insights into the mechanistic model of RBM10-mediated splicing regulation and established genomic resources for future studies on its function in different pathophysiological contexts. We sequenced the mRNA of HEK293 cells and LCL cells, and we determined the RBM10 binding sites using PARCLIP in HEK293 cells. In total we sequenced four mRNA-Seq libraries for KD and two for OE in HEK293 cells; for each of these libraries, we also sequenced one control library. We also sequenced the mRNA of one patient LCL and two normal LCL libraries. Two replicates of PARCLIP sequencing were perfomed.
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Project description:Several different YAP1 gene fusions have been identified in various human cancers. We performed RNA sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3, as well as on whole tumor lysates from mouse brain tumors generated by intra-cranial expression of either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3.
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Project description:Several different YAP1 gene fusions have been identified in various human cancers. We performed RNA sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3, as well as on whole tumor lysates from mouse brain tumors generated by intra-cranial expression of either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3.
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