Abstract
The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease.
Highlights
Multiple myeloma (MM) is an incurable plasma cell neoplasm that affects over 20,000 people per year in the US alone
To better understand the impact of UCH-L1 expression in human myeloma, we analyzed RNA expression profiling data in a large cohort (n = 351) of newly diagnosed patients who were treated on the Total Therapy 2 (TT2) protocol that added thalidomide onto a background of tandem autologous stem cell transplants [26]
The effect of UCH-L1 on survival was lost in patients treated on Total Therapy 3 (TT3; n = 208), a regimen that incorporated bortezomib onto this backbone (Figure 1B)
Summary
Multiple myeloma (MM) is an incurable plasma cell neoplasm that affects over 20,000 people per year in the US alone. A series of novel therapeutic agents, coupled with improved care for patients undergoing autologous stem cell transplantation has led to dramatic improvements in the progression free survival for individuals with MM [1, 2]. While impressive, these treatments are often accompanied by substantial toxicities, necessitating the search for targeted therapies in the hope of continuing advances while reducing adverse effects. The proteasome has proven a highly efficacious target in MM over the last decade since approval of the first in class inhibitor bortezomib [3,4,5] This led to the realization that the ubiquitin-proteasome system plays an important role in this and other cancers. It is likely that there are specific alterations within the components of the UPS that are disrupted in myeloma pathogenesis – the targeting of which may allow more specific and less toxic therapeutic options in this disease
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