Expression of Possible Targets for New Proteasome Inhibitors in Diffuse Large B-cell Lymphoma

Eur J Haematol. 2017 Jan;98(1):52-56. doi: 10.1111/ejh.12784. Epub 2016 Jul 12.

Abstract

Objectives: Investigating expression of possible targets for proteasome inhibitors in patients with diffuse large B-cell lymphoma (DLBCL) and correlating the findings to clinical parameters and outcome.

Methods: Tumour material from 92 patients with DLBCL treated with either R-CHOP like (n = 69) or CHOP like (n = 23) regimens were stained for possible targets of proteasome inhibitors.

Results: The primary target molecule of bortezomib, proteasome subunit beta, type 5 (PSMB5), was not detected in the tumour cells in any of the cases but showed an abundant expression in cells in the microenvironment. However, the deubiquitinases (DUBs) of the proteasome, the ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) and the ubiquitin specific peptidase 14 (USP14), were detected in the cytoplasm of the tumour cells in 77% and 74% of the cases, respectively. The adhesion regulating molecule 1 (ADRM1) was detected in 98% of the cases. There was no correlation between the expression of any of the studied markers and clinical outcome or GC/non-GC phenotype.

Conclusions: We suggest that UCHL5 and/or USP14 should be further evaluated as new targets for proteasome inhibitors in DLBCL. The lack of expression of PSMB5 on the tumour cells might provide an explanation of the relatively poor results of bortezomib in DLBCL.

Keywords: UCHL5; USP14; proteasome inhibitors.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide / therapeutic use
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / diagnosis
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prednisone / therapeutic use
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use*
  • Rituximab
  • Treatment Outcome
  • Ubiquitin Thiolesterase / antagonists & inhibitors
  • Vincristine / therapeutic use
  • Young Adult

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Agents
  • Proteasome Inhibitors
  • R-CHOP protocol
  • USP14 protein, human
  • Rituximab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • UCHL5 protein, human
  • Ubiquitin Thiolesterase
  • Proteasome Endopeptidase Complex
  • Prednisone

Supplementary concepts

  • CHOP protocol