title: Cytochrome c-related caspase-3 activation determines treatment response and relapse in childhood precursor B-cell ALL.
abstract: Deficient activation of apoptosis signaling pathways may be responsible for treatment failure in acute leukemia. Here, we address the impact of intact apoptosis signaling in 78 patients with pediatric precursor B-cell acute lymphoblastic leukemia (ALL) by analysis of 2 key apoptogenic events: caspase-3 activation and cytochrome c release in leukemia cells cultured in vitro. Both events correlated only in the group of patients who had a good response and patients in continuous remission, suggesting that intact apoptosis signaling is a characteristic for favorable outcome. By combining both parameters, we identified a novel indicator, cytochrome c-related activation of caspase-3 (CRAC). CRAC directly connects the extent of caspase-3 activation to cytochrome c release in single cells in an individual patient sample. In CRAC-positive patients, indicating proficient apoptosis signaling, the number of persisting leukemia cells on day 15 was significantly lower than in the CRAC-negative patient group (n = 27, mean 6.0% versus n = 36, mean 22.6%; P = .003). At a median follow-up of 31 months, disease-free survival was 84 months (95% CI = 76 to 91 months) and 66 months (95% CI = 52 to 80 months) for patients with positive and negative CRAC, respectively (P = .019). CRAC may serve as a functionally defined risk factor for treatment stratification.
authors.affiliation: Universitätsklinik für Kinder-und Jugendmedizin, University of Ulm, Germany.
authors.forename: Lüder Hinrich
authors.initials: LH
authors.lastname: Meyer
authors.forename: Leonid
authors.initials: L
authors.lastname: Karawajew
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Karsten
authors.initials: K
authors.lastname: Stahnke
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D045304:Cytochromes c / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011379:Prognosis; D012008:Recurrence; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases