Intact apoptosis signaling in myeloid leukemia cells determines treatment outcome in childhood AML.
Recently we reported that intact apoptosis signaling is indicative of favorable outcome in childhood acute lymphoblastic leukemia. Here we addressed this issue in 45 pediatric acute myeloid leukemia patients analyzing 2 core apoptogenic events: cytochrome c release and caspase-3 activation. In patients with good prognosis cytochrome c release was clearly found to be caspasedependent and correlated with activated caspase-3, indicating that activation of initiator or amplifier caspases such as caspase-8 together with an intact apoptosome function are elementary for favorable outcome. The functional integrity of this apoptogenic checkpoint is reflected by the parameter caspase-dependent cytochrome c-related activation of caspase-3 (CRAC(dep)). Patients with positive CRAC(dep) values (intact signaling) exhibited superior survival compared with CRAC(dep) negative patients (deficient signaling). Thus, the propensity to undergo apoptosis of leukemia cells is an important feature for favorable treatment outcome and may serve as an additional stratification tool for pediatric AML patients. This trial was registered at www.ClinicalTrials.gov as #NCT00111345.
Meyer
Lüder H
LH
Department of Paediatrics and Adolescent Medicine, University of Ulm, Eythstrasse 24, Ulm, Germany.
Queudeville
Manon
M
Eckhoff
Sarah M
SM
Creutzig
Ursula
U
Reinhardt
Dirk
D
Karawajew
Leonid
L
Ludwig
Wolf-Dieter
WD
Stahnke
Karsten
K
Debatin
Klaus-Michael
KM
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002648:Child; D045304:Cytochromes c / Q000378:metabolism; D018572:Disease-Free Survival; D004789:Enzyme Activation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology* / Q000628:therapy*; D012074:Remission Induction; D012307:Risk Factors; D015398:Signal Transduction; D016896:Treatment Outcome
D045304:Cytochromes c; D053148:Caspase 3