title: UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression.
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.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Bedekovics
authors.affiliation: Division of Hematology-Oncology, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Division of Hematology-Oncology, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.|Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Galardy
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase
keywords: UCH-L1; biomarker; deubiquitinating enzymes; mouse model; myeloma