Proteasome enzymatic activities in plasma as risk stratification of patients with acute myeloid leukemia and advanced-stage myelodysplastic syndrome.
OBJECTIVE
Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification.


METHODS
We assessed the utility of measuring pretreatment proteasome chymotrypsin-like, caspase-like, and trypsin-like activities in plasma to predict response and survival of patients with AML (n = 174) or advanced-stage MDS (n = 52).


RESULTS
All three enzymatic activities were significantly (P < 0.001) increased in the plasma of patients with AML and MDS compared with normal controls. Both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, correlated with outcome. Chymotrypsin-like and caspase-like activities, but not trypsin-like activity, predicted response in univariate analysis (P = 0.002). However, only chymotrypsin-like activity was independent predictor of response from age grouping (<70 versus > or =70 years), cytogenetics, and blood urea nitrogen in multivariate analysis. Similarly, both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, were predictors of overall survival in univariate analysis (P < 0.0001), but only chymotrypsin-like activity was independent of cytogenetics, age, performance status, blood urea nitrogen, and beta(2)-microglobulin in multivariate Cox regression models. Chymotrypsin-like activity was also a strong independent predictor of survival in patients with intermediate karyotype (n = 124).


CONCLUSIONS
Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
Ma
Wanlong
W
Department of Hematopathology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California, USA.
Kantarjian
Hagop
H
Bekele
Benjamin
B
Donahue
Amber C
AC
Zhang
Xi
X
Zhang
Zhong J
ZJ
O'Brien
Susan
S
Estey
Elihu
E
Estrov
Zeev
Z
Cortes
Jorge
J
Keating
Michael
M
Giles
Francis
F
Albitar
Maher
M
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020169:Caspases / Q000097:blood / Q000378:metabolism; D002918:Chymotrypsin / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes / Q000097:blood* / Q000201:enzymology / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000097:blood* / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D014357:Trypsin / Q000097:blood / Q000378:metabolism; D055815:Young Adult
D002918:Chymotrypsin; D014357:Trypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex