UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression
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Sajjad Hussain1, Tibor Bedekovics1, Marta Chesi2, P. Leif Bergsagel2, Paul J. Galardy1,3
1Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
2Division of Hematology-Oncology, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA
3Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN, USA
Paul J. Galardy, e-mail: [email protected]
Keywords: UCH-L1, deubiquitinating enzymes, myeloma, mouse model, biomarker
Received: April 07, 2015 Accepted: September 19, 2015 Published: October 19, 2015
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.
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