UCHL1 is a Biomarker of Aggressive Multiple Myeloma Required for Disease Progression

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Oct 30

PMID 26513019

Citations 22

Authors

Sajjad Hussain

Tibor Bedekovics

Marta Chesi

P Leif Bergsagel

Paul J Galardy

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Hanamura I, Huang Y, Zhan F, Barlogie B, Shaughnessy J . Prognostic value of cyclin D2 mRNA expression in newly diagnosed multiple myeloma treated with high-dose chemotherapy and tandem autologous stem cell transplantations. Leukemia. 2006; 20(7):1288-90. DOI: 10.1038/sj.leu.2404253. View

Palumbo A, Anderson K . Multiple myeloma. N Engl J Med. 2011; 364(11):1046-60. DOI: 10.1056/NEJMra1011442. View

Shah J, Orlowski R . Proteasome inhibitors in the treatment of multiple myeloma. Leukemia. 2009; 23(11):1964-79. PMC: 4737506. DOI: 10.1038/leu.2009.173. View

Ovaa H, Kessler B, Rolen U, Galardy P, Ploegh H, Masucci M . Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci U S A. 2004; 101(8):2253-8. PMC: 356937. DOI: 10.1073/pnas.0308411100. View

Neff B, Voss S, Allen C, Schroeder M, Driscoll C, Link M . Bioluminescent imaging of intracranial vestibular schwannoma xenografts in NOD/SCID mice. Otol Neurotol. 2008; 30(1):105-11. PMC: 3918230. DOI: 10.1097/MAO.0b013e31818b6cea. View

Hyun T, Yam A, Pece S, Xie X, Zhang J, Miki T . Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood. 2000; 96(10):3560-8. View

Zhu J, Wang M, Yu Y, Qi H, Han K, Tang J . A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma. Oncotarget. 2014; 6(1):185-95. PMC: 4381587. DOI: 10.18632/oncotarget.2688. View

Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C . Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006; 107(10):4053-62. PMC: 1895278. DOI: 10.1182/blood-2005-08-3434. View

Chauhan D, Hideshima T, Anderson K . Targeting proteasomes as therapy in multiple myeloma. Adv Exp Med Biol. 2008; 615:251-60. DOI: 10.1007/978-1-4020-6554-5_12. View

10.

Chauhan D, Tian Z, Nicholson B, Kumar K, Zhou B, Carrasco R . A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012; 22(3):345-58. PMC: 3478134. DOI: 10.1016/j.ccr.2012.08.007. View

11.

Tomko Jr R, Hochstrasser M . Molecular architecture and assembly of the eukaryotic proteasome. Annu Rev Biochem. 2013; 82:415-45. PMC: 3827779. DOI: 10.1146/annurev-biochem-060410-150257. View

12.

Mimura N, Hideshima T, Shimomura T, Suzuki R, Ohguchi H, Rizq O . Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res. 2014; 74(16):4458-69. PMC: 4140659. DOI: 10.1158/0008-5472.CAN-13-3652. View

13.

Hussain S, Feldman A, Das C, Ziesmer S, Ansell S, Galardy P . Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor. Mol Cell Biol. 2013; 33(6):1188-97. PMC: 3592026. DOI: 10.1128/MCB.01389-12. View

14.

Li F, Xu Y, Deng P, Yang Y, Sui W, Jin F . Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma. Oncotarget. 2015; 6(11):9434-44. PMC: 4496228. DOI: 10.18632/oncotarget.3319. View

15.

Tian Z, Darcy P, Wang X, Ray A, Tai Y, Hu Y . A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood. 2013; 123(5):706-16. PMC: 3907756. DOI: 10.1182/blood-2013-05-500033. View

16.

Gavioli R, Frisan T, Vertuani S, Bornkamm G, Masucci M . c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol. 2001; 3(3):283-8. DOI: 10.1038/35060076. View

17.

Zhu Y, Braggio E, Shi C, Bruins L, Schmidt J, Van Wier S . Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011; 118(18):4771-9. PMC: 3208291. DOI: 10.1182/blood-2011-05-356063. View

18.

Kuo A, Cheung P, Chen K, Zee B, Kioi M, Lauring J . NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell. 2011; 44(4):609-20. PMC: 3222870. DOI: 10.1016/j.molcel.2011.08.042. View

19.

Chesi M, Nardini E, Lim R, Smith K, Kuehl W, Bergsagel P . The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998; 92(9):3025-34. View

20.

Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng W, Roels S . Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood. 2006; 109(8):3177-88. DOI: 10.1182/blood-2006-09-044974. View