Project description:DUSP4 deficiency due to promoter hypermethylation drives oncogenic JNK signaling and tumor cell survival in diffuse large B-cell lymphoma
Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. A methylation profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2926: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2926/
Project description:The epigenetic dysregulation of tumor suppressor genes is a major driver of human carcinogenesis. We have combined genome-wide methylation analyses with functional screening to identify novel candidate tumor suppressor genes in diffuse large B-cell lymphoma (DLBCL). We find that the dual-specificity phosphatase DUSP4 is aberrantly silenced in nodal and extranodal DLBCL due to promoter hypermethylation; ectopic expression of wild type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. JNK inhibition prevents DLBCL survival in vitro and in vivo, and synergizes strongly with inhibitors of chronic active B-cell receptor signaling. Our results provide a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, alone or in synthetic lethal combinations. RNA-seq expression profiling data set related to this experiment was also deposited at ArrayExpress under accession number E-MTAB-2925: http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2925/
Project description:We studied the DNA methylation profiles of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n=66), High-grade B-cell lymphoma (n=7), Primary CNS lymphoma (n=8), and transformation of indolent B-cell lymphoma (n=12). One sample of normal GC B-cells from tonsils was included as a control. LBCL cases had a particularly aberrant semimethylated pattern with large intertumor variation and overall low hypermethylation. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation was independently associated with worse disease-specific survival and progression-free survival.
Project description:Transcription profiling of human T-cell lymphoblastic leukemia, acute mylelogenous leukemia and Diffuse Large Cell Lymphoma cell lines after treatment with aplidin and/or cytarabine
Project description:The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. METHODS: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. RESULTS: Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators.
Project description:Plasmablastic lymphoma is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology anda plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the profile of chromosomal alterations is not well known.
