Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia.
Recent studies have suggested that variations in levels of caspases, a family of intracellular cysteine proteases, can profoundly affect the ability of cells to undergo apoptosis. In this study, immunoblotting was used to examine levels of apoptotic protease activating factor-1 (Apaf-1) and procaspases-2, -3, -7, -8, and -9 in bone marrow samples (at least 80% leukemia) harvested before chemotherapy from adults with newly diagnosed acute myelogenous leukemia (AML, 42 patients) and acute lymphocytic leukemia (ALL, 18 patients). Levels of each of these polypeptides varied over a more than 10-fold range between specimens. In AML samples, expression of procaspase-2 correlated with levels of Apaf-1 (R(s) = 0.52, P <.02), procaspase-3 (R(s) = 0.56, P <.006) and procaspase-8 (R(s) = 0.64, P <.002). In ALL samples, expression of procaspases-7 and -9 was highly correlated (R(s) = 0.90, P <.003). Levels of these polypeptides did not correlate with prognostic factors or response to induction chemotherapy. In further studies, 16 paired samples (13 AML, 3 ALL), the first harvested before induction therapy and the second harvested at the time of leukemia regrowth, were also examined. There were no systematic alterations in levels of Apaf-1 or procaspases at relapse compared with diagnosis. These results indicate that levels of initiator caspases vary widely among different leukemia specimens but cast doubt on the hypothesis that this variation is a major determinant of drug sensitivity for acute leukemia in the clinical setting. (Blood. 2000;96:3922-3931)
Svingen
P A
PA
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Karp
J E
JE
Krajewski
S
S
Mesner
P W
PW
Gore
S D
SD
Burke
P J
PJ
Reed
J C
JC
Lazebnik
Y A
YA
Kaufmann
S H
SH
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D053477:Apoptotic Protease-Activating Factor 1; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000737:chemistry / Q000201:enzymology; D020169:Caspases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015331:Cohort Studies; D004792:Enzyme Precursors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000378:metabolism / Q000628:therapy; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000378:metabolism; D011379:Prognosis; D011506:Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D014408:Biomarkers, Tumor; D004792:Enzyme Precursors; D011506:Proteins; D020169:Caspases