UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

Abstract

• The neuronal marker UCH-L1 is induced in, and specifically augments the oncogeneinduced transformation of, GCB cells.• High levels of UCHL1 identify patients with GC DLBCL with an increased risk for poor outcomes.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. (Blood. 2016;127(12):1564-1574

Ubiquitin C‐Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine‐Based Inhibitor

“…UCHL1 levels of expression and enzymatic activity are correlated with increased metastatic behavior in various cancers, including small‐cell lung cancer, myeloma, and lymphoma –. Three cell lines were selected to evaluate the efficacy of compound 1 based on their sensitivity to genetic depletion of UCHL1: SW1271 (small‐cell lung cancer line), KMS11, and KMS12 (myeloma cell lines).…”

UCH‐L1 promotes invasion of breast cancer cells through activating Akt signaling pathway

“…As a de-ubiquitination enzyme, UCH-L1 is considered as a tumor promoting protein in many human tumors. [16][17][18][19][20][21][22][23][24] However, the function of UCH-L1 in tumor initiation, progression and invasion is still controversial, as UCH-L1 has also been found to be downregulated in other tumor types including prostate cancer, 47 ovarian cancer, 48 and nasopharyngeal cancer. 49 Therefore, the potential role of UCH-L1 as an oncogene or a tumor suppressor may be cell context or tissue specific.…”

“…A series elegant in vivo studies from the same group also highlighted a role of UCH-L1 on activating Akt signaling through different molecular mechanisms without alterating expression level of total Akt protein. [18][19][20]57 In addition, many studies have demonstrated that regulation of Akt is mainly through caspase-mediated degradation and heat shock protein-mediated protein stabilization, while only few studies suggested Akt might be degraded by ubiquitin-proteasom system (UPS) (summarized in the review article 58 ). Thus, it is unlikely that UCH-L1 activates Akt signaling pathway by de-ubiquitinating and stabilizing Akt.…”

“…11,12 Extensive studies have also demonstrated that activity and solubility alterations of UCH-L1 can cause neurodegenerative diseases. [13][14][15] Despite its expression level is low in other tissues, overexpression of UCH-L1 has been found in some cancers, including pancreatic cancer, 16,17 myeloma and lymphoma, [18][19][20][21] prostate cancer, 22 neuroblastoma, 23 and osteosarcoma. 24 Furthermore, expression of UCH-L1 has been shown to be positively correlated with cancer cell chemotherapy resistance, 25,26 metastasis, 27 and negatively correlated with prognosis of cancer patients.…”

UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice

“…9 Encoding a small (25 kDa) deubiquitinating enzyme, transgenic expression of Uchl1 is sufficient to drive spontaneous B-cell lymphomagenesis in mice and accelerate disease in the Em-myc model. 10,11 We uncovered a previously unrecognized function of UCH-L1 in reorganizing mTOR-AKT signaling both in cell lines and in mice. 12 UCH-L1 disrupts the ubiquitination of the mTORC1 subunit raptor that is required for its stable association with mTOR, leading to reduced levels of mTORC1.…”