title: Enzymatic activity of circulating proteasomes correlates with clinical behavior in patients with chronic lymphocytic leukemia.
abstract: BACKGROUND
  The ubiquitin-proteasome pathway has been implicated in the pathogenesis of many hematologic malignancies.
  
  
  METHODS
  The authors measured proteasome peptidase activity levels in plasma samples from 225 patients with chronic lymphocytic leukemia (CLL) and correlated the results with clinical behavior. By using fluorogenic kinetic assays, the enzymatic activity levels of 3 proteasomes were measured: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L).
  
  
  RESULTS
  All activity levels were significantly higher in patients who had CLL compared with the levels in a control group of healthy volunteers (P<.001). Rai stage was correlated with Ch-L activity (P<.001) but not with Cas-L or Tr-L activity. Levels of beta2 microglobulin (B2M) were correlated with Ch-L activity (correlation coefficient [R]=0.4; P<.001) and with Cas-L activity (R=0.25; P=.001) but not with Tr-L activity. Cas-L activity as a continuous variable was a strong predictor of survival. Ch-L and Cas-L activity levels as categorical variables both were strong predictors of survival; Cas-L activity was independent of B2M level but not of immunoglobulin variable heavy chain gene (IgVH) mutation status. However, the combination of elevated B2M levels (>3.2 mg/L) and Cas-L activity (>1.32 pmoL/second/mL plasma) was associated with significantly shorter survival independent of IgVH mutation status.
  
  
  CONCLUSIONS
  The current results indicated that measuring plasma proteasome activity has prognostic value in CLL that, when combined with B2M, can be independent of IgVH mutation status.
authors.affiliation: Department of Hematology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92675, USA.
authors.forename: Wanlong
authors.initials: W
authors.lastname: Ma
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Iman
authors.initials: I
authors.lastname: Jilani
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D020169:Caspases / Q000097:blood*; D002918:Chymotrypsin / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000097:blood / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000097:blood*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014357:Trypsin / Q000097:blood*; D001613:beta 2-Microglobulin / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger; D001613:beta 2-Microglobulin; D002918:Chymotrypsin; D014357:Trypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex