Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
BAP1 loss defines a new class of renal cell carcinoma.
Sex, Age, Specimen part, Disease, Disease stage, Subject
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LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas.
Specimen part, Cell line, Treatment
View SamplesUsing different surface markers it has been possible to isolate lymphoid lineage-biased progentors and test their potential in vivo and in vitro. Here we apply single cell sequencing of lymphoid progenitors to obtain further insights into differentiation and commitment to the lymphoid lineage. Overall design: Single cells from the bone marrow from various stages during lymphoid differentiation were sorted into 384-well plates based on their surface marker expression of Flt3, Sca-1 and c-Kit and processed using a modified version of the CEL-Seq2 protocol (Hashimshony et al. 2016, Genome Biology, DOI: 10.1186/s13059-016-0938-8). In addition the original version of the CEL-Seq2 protoco and thel modified versions with different volume reductions and were compared using murine embryonic stem cells.
FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data.
Specimen part, Cell line, Subject
View SamplesProper regulation of nuclear factor B (NF-B) transcriptional activity is required for normal lymphocyte function, and deregulated NF-B signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-Binducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-B signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-B pathway in B lymphoproliferative disease.
Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
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View SamplesComparison of t(11;18)-positive MALT lymphoma to t(11;18)-negative MALT lymphoma, with a special focus on the NF-KB pathway and it's targets
Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
Specimen part
View SamplesCitrus greening or huanglongbing (HLB) is a devastating disease of citrus. HLB is associated with the phloem-limited fastidious prokaryotic alpha-proteobacterium Candidatus Liberibacter spp. In this report, we used sweet orange (Citrus sinensis) leaf tissue infected with 'Ca. Liberibacter asiaticus' and compared this with healthy controls.
Response of sweet orange (Citrus sinensis) to 'Candidatus Liberibacter asiaticus' infection: microscopy and microarray analyses.
Specimen part
View SamplesIn this study we focussed on malignant post-transplant lymphomas.
Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.
Specimen part
View SamplesTumor cells were microdissected from frozen sections of NLPHL and THRLBCL. RNA was amplified using the NUGEN WT-Ovation-One-direct-Kit. Samples were compared to tonsilar germinal center CD77 B cells.
Nodular lymphocyte predominant hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma--endpoints of a spectrum of one disease?
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.
Specimen part, Disease
View SamplesAttempts at modeling chromosomal translocations involving MALT1 gene, hallmarks of human mucosa-associated lymphoid tissue (MALT) lymphoma, have failed to reproduce the disease in mice. Here we describe a transgenic model in which MALT1 expression was targeted to mouse hematopoietic stem/progenitor cells. In Sca1-MALT1 mice, MALT1 deregulation activated the NF-kappaB pathway in Sca1+ cells, promoting selective B-cell differentiation and mature lymphocyte accumulation in extranodal tissues, progressively leading to the development of clonal B-cell lymphomas. These tumors recapitulated the histopathological features of human MALT lymphomas, presenting typical lymphoepithelial lesions and plasmacytic differentiation. Transcriptional profiling of Sca1-MALT1 murine lymphomas revealed overlapping molecular signatures with human MALT lymphomas, including MALT1-mediated NF-kappaB activation, pro-inflammatory signaling and XBP1-induced plasmacytic differentiation. Moreover, murine Malt1 showed proteolytic activity by cleaving Bcl10 in Sca1-MALT1 lymphomas. Our novel technological approach has allowed modeling human MALT lymphoma in mice, which represent unique tools study MALT lymphoma biology and evaluate anti-MALT1 therapies.
Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.
Specimen part, Disease
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