title: UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma.
abstract: Gene expression profiling has identified 2 major subclasses of diffuse large B-cell lymphoma (DLBCL). Cases resembling germinal center (GC) B cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-GC cells (activated B-cell DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here, we show that UCH-L1 reflects GC lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in GC B cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. We also find that UCH-L1 cooperates with BCL6 in a mouse model of GC B-cell lymphoma, but not with the development of multiple myeloma derived from post-GC cells. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biological diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in GC B cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL.
authors.affiliation: Department of Pediatric and Adolescent Medicine.
authors.forename: Tibor
authors.initials: T
authors.lastname: Bedekovics
authors.affiliation: Department of Pediatric and Adolescent Medicine.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.affiliation: Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology-Oncology, and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Galardy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; C482860:UCHL1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse