4.3 Article

UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

Journal

ONCOTARGET
Volume 6, Issue 38, Pages 40704-40718

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5727

Keywords

UCH-L1; deubiquitinating enzymes; myeloma; mouse model; biomarker

Funding

  1. NIH [CA151351-01]
  2. Howard Hughes Medical Institute Physician Scientist Early Career Award
  3. Gabrielle's Angels Cancer Research Foundation
  4. Multiple Myeloma Research Foundation
  5. Mayo Foundation

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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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