title: DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.
abstract: The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. 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. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.
authors.affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Corina A
authors.initials: CA
authors.lastname: Schmid
authors.affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Robinson
authors.affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Scheifinger
authors.affiliation: Institute of Food, Nutrition, and Health and Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zürich (ETHZ), 8093 Zürich, Switzerland Institute of Food, Nutrition, and Health and Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zürich (ETHZ), 8093 Zürich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute of Pathology, Cantonal Hospital of St. Gallen, 9007 St. Gallen, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Cogliatti
authors.affiliation: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institute of Molecular Cancer Research, Institute of Molecular Life Sciences, and Swiss Institute of Bioinformatics (SIB), University of Zürich, 8057 Zürich, Switzerland mueller@imcr.uzh.ch.
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases / Q000172:deficiency*; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000172:deficiency*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D048670:MAP Kinase Kinase 4; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases
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