Enzymatic activity of circulating proteasomes correlates with clinical behavior in patients with chronic lymphocytic leukemia.
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.
Ma
Wanlong
W
Department of Hematology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92675, USA.
Kantarjian
Hagop
H
O'Brien
Susan
S
Jilani
Iman
I
Zhang
Xi
X
Estrov
Zeev
Z
Ferrajoli
Alessandra
A
Keating
Michael
M
Giles
Francis
F
Albitar
Maher
M
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
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