Using UCH-L1 to Identify Patients with Aggressive Germinal Center Diffuse Large B-Cell Lymphoma
Gene expression profiling has identified two major subclasses of diffuse large B-cell lymphoma. Cases resembling (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-germinal center cells (ABC-DLBCL).
In a previous study, Mayo Clinic researchers found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. However, the cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown.
In a new study published in the journal Blood, Mayo Clinic researchers demonstrate that UCH-L1 reflects germinal center in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL.
Researchers found that UCH-L1 is specifically induced in germinal center B-cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. The study also indicated that UCH-L1 cooperates with BCL6 in a mouse model of germinal center B-cell lymphoma, but not with the development of multiple myeloma derived from post-germinal center cells.
Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biologic diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in germinal center B-cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication.
These results 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.