Catalytically Active UCH-L1 Is Required for MYC Driven B-Cell Lymphomagenesis

Mature B-cell lymphomas are common in children and adults. While increasing biological knowledge has greatly improved the classification of these diseases, the ability to stratify therapy based on this knowledge is limited. As the outcomes for patients with relapsed/refractory disease is poor, it is important to optimize the upfront approach to these patients making enhanced biomarker discovery essential. We recently found that the de-ubiquitinase UCH-L1 is strongly induced in normal GC B-cells, is highly expressed in germinal center type diffuse large B-cell lymphoma, and is a potent prognostic factor associated with poor outcomes in this disease. Using transgenic mice (Uchl1^Tg), we observed that deregulated UCH-L1 drives spontaneous B-cell lymphomagenesis and significantly accelerates disease when combined with the Iμ-HABCL6 or Eμ- myc models of GC derived lymphoma. At the molecular level, we showed that UCH-L1 regulates mTOR complex assembly and promotes AKT signaling. It has been alternatively hypothesized that stabilization of mono-ubiquitin is an essential function of UCH-L1 - a mechanism that does not require catalytic activity. To determine the impact of UCH-L1 catalytic activity on lymphoma development, we generated mice carrying a catalytically inactive transgene (Uchl1^TgC90A). Consistent with our prior work, we observed that UCH-L1 promotes AKT phosphorylation and suppresses mTORC1 activity towards 4EBP1 and S6K in splenocytes in a manor dependent on catalytic activity. To examine the impact on lymphomagenesis, we crossed Uchl1^Tg and Uchl1^TgC90A mice with the Eμ- myc model. While we again found the wild-type transgene to accelerate Myc driven lymphoma development, there was no such effect of the C90A construct, indicating that the catalytic activity of UCH-L1 is required for its oncogenic activity. To further examine its role in MYC driven lymphomagenesis we crossed Eμ- myc mice with homozygous null Uchl1 mice and found that Uchl1 loss leads to a significant improvement in lymphoma free survival, indicating that UCH-L1 is a key cooperating factor with MYC in lymphoma. Consistent with this, gene expression profiling from lymphomas arising in Uchl1^Tg mice share a striking similarity to those driven by MYC and constitutive PI3 kinase signaling (MYC/P110*) but are distinct from those seen in Iμ-HABCL6 or Lig4 null mice. These data indicate an mechanistic interplay between UCH-L1 and MYC in B-cell lymphoma and suggest that UCH-L1 inhibition may be an effective approach in B-cell lymphomas expressing MYC.