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

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.

[1]  K. Ru,et al.  Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma , 2015, Oncotarget.

[2]  M. Sonobe,et al.  UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α , 2015, Nature Communications.

[3]  X. Mao,et al.  A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma , 2014, Oncotarget.

[4]  N. Donato,et al.  Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. , 2014, Cancer research.

[5]  A. Iwama,et al.  Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. , 2014, Cancer research.

[6]  Guoan Chen,et al.  Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms , 2013, Oncotarget.

[7]  M. Hochstrasser,et al.  Molecular architecture and assembly of the eukaryotic proteasome. , 2013, Annual review of biochemistry.

[8]  K. Uchida,et al.  Ubiquitin C-terminal Hydrolase L1 (UCH-L1) Acts as a Novel Potentiator of Cyclin-dependent Kinases to Enhance Cell Proliferation Independently of Its Hydrolase Activity* , 2013, The Journal of Biological Chemistry.

[9]  Michael J. Schell,et al.  Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. , 2013, Cell reports.

[10]  A. Feldman,et al.  Ubiquitin Hydrolase UCH-L1 Destabilizes mTOR Complex 1 by Antagonizing DDB1-CUL4-Mediated Ubiquitination of Raptor , 2013, Molecular and Cellular Biology.

[11]  Ying Zhang,et al.  USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. , 2012, The Journal of clinical investigation.

[12]  Parantu K. Shah,et al.  A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. , 2012, Cancer cell.

[13]  J. Hurst-Kennedy,et al.  Ubiquitin C-Terminal Hydrolase L1 in Tumorigenesis , 2012, Biochemistry research international.

[14]  M. Rapé,et al.  The Ubiquitin Code , 2012, Annual review of biochemistry.

[15]  Alexander Varshavsky,et al.  The ubiquitin system, an immense realm. , 2012, Annual review of biochemistry.

[16]  B. Garcia,et al.  NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. , 2011, Molecular cell.

[17]  P. L. Bergsagel,et al.  Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. , 2011, Blood.

[18]  J. V. van Deursen,et al.  Overexpression of Ubiquitin Specific Protease 44 (USP44) Induces Chromosomal Instability and Is Frequently Observed in Human T-Cell Leukemia , 2011, PloS one.

[19]  L. Staudt,et al.  The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. , 2011, Blood.

[20]  N. Donato,et al.  Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. , 2010, Cancer research.

[21]  S. Perkins,et al.  The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling , 2010, Leukemia.

[22]  Toshihiko Ogura,et al.  Identification of a Primary Target of Thalidomide Teratogenicity , 2010, Science.

[23]  M. Caplow,et al.  Ubiquitin editing enzyme UCH L1 and microtubule dynamics: Implication in mitosis , 2010, Cell cycle.

[24]  R. Orlowski,et al.  Proteasome inhibitors in the treatment of multiple myeloma , 2009, Leukemia.

[25]  W. Yue,et al.  Positive Reciprocal Regulation of Ubiquitin C-Terminal Hydrolase L1 and β-Catenin/TCF Signaling , 2009, PloS one.

[26]  Ying Zhang,et al.  DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors , 2009, Cell cycle.

[27]  J. Sarkaria,et al.  Bioluminescent Imaging of Intracranial Vestibular Schwannoma Xenografts in NOD/SCID Mice , 2009, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[28]  D. Chauhan,et al.  Targeting the UPS as therapy in multiple myeloma , 2008, BMC Biochemistry.

[29]  D. Dingli,et al.  Improved survival in multiple myeloma and the impact of novel therapies. , 2008, Blood.

[30]  Anthony Boral,et al.  Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. , 2006, Blood.

[31]  P. L. Bergsagel,et al.  MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. , 2006, Blood.

[32]  Yongsheng Huang,et al.  A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. , 2006, Blood.

[33]  Yan Tang,et al.  CHIR-258 Is Efficacious in A Newly Developed Fibroblast Growth Factor Receptor 3–Expressing Orthotopic Multiple Myeloma Model in Mice , 2006, Clinical Cancer Research.

[34]  F. Zhan,et al.  Prognostic value of Cyclin D2 mRNA expression in newly diagnosed multiple myeloma treated with high-dose chemotherapy and tandem autologous stem cell transplantations , 2006, Leukemia.

[35]  Hiroshi Yasui,et al.  Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. , 2005, Blood.

[36]  Bart Barlogie,et al.  Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. , 2005, Blood.

[37]  T. Sugihara,et al.  Expression of protein gene product 9·5 (PGP9·5)/ubiquitin‐C‐terminal hydrolase 1 (UCHL‐1) in human myeloma cells , 2004, British journal of haematology.

[38]  H. Ploegh,et al.  Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Peter T Lansbury,et al.  Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. , 2003, Chemistry & biology.

[40]  D. Chauhan,et al.  Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma , 2001, Oncogene.

[41]  M. Masucci,et al.  c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells , 2001, Nature Cell Biology.

[42]  A. Lichtenstein,et al.  The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. , 2000, Cancer research.

[43]  J. Gutkind,et al.  Loss of PTEN expression leading to high Akt activation in human multiple myelomas. , 2000, Blood.

[44]  K D Wilkinson,et al.  The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. , 1989, Science.

[45]  Raghupathy,et al.  Proteasome Inhibitors in the Treatment of Multiple Myeloma , 2016 .

[46]  P. Richardson,et al.  A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. , 2014, Blood.

[47]  D. Chauhan,et al.  Targeting proteasomes as therapy in multiple myeloma. , 2008, Advances in experimental medicine and biology.

[48]  P. L. Bergsagel,et al.  The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. , 1998, Blood.

[49]  O. Cope,et al.  Multiple myeloma. , 1948, The New England journal of medicine.