Hussain Sajjad, Bedekovics Tibor, Chesi Marta, Bergsagel P Leif, Galardy Paul J
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
Division of Hematology-Oncology, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
Oncotarget. 2015 Dec 1;6(38):40704-18. doi: 10.18632/oncotarget.5727.
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.
蛋白酶体抑制在多发性骨髓瘤中的成功凸显了泛素-蛋白酶体系统（UPS）在该疾病中的关键作用。然而，在寻找UPS中参与骨髓瘤发病机制的更特异性靶点方面进展甚微。我们之前发现泛素水解酶UCH-L1在包括骨髓瘤在内的B细胞恶性肿瘤中经常过度表达，并表明它在小鼠中是一种有效的癌基因。在此我们表明UCH-L1是一种不良预后因素，对骨髓瘤的进展至关重要。我们发现高水平的UCHL1可预测新诊断患者的早期进展；硼替佐米的加入可逆转这一发现。我们还发现高UCHL1水平是硼替佐米在复发患者中优于高剂量地塞米松的关键因素。高UCHL1与包括4p16重排和1q21扩增在内的已知遗传风险部分重叠，但又有所不同。使用原位小鼠模型，我们发现敲除UCH-L1可延缓骨髓瘤的扩散并使已形成的疾病消退。我们得出结论，UCH-L1是侵袭性骨髓瘤的生物标志物，可能是硼替佐米反应的重要标志物，并且其本身可能是播散性疾病的有效靶点。
