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 Blood, 1 March 2008, Vol. 111, No. 5, pp. 2899-2903.
Prepublished online as a Blood First Edition Paper on December 14, 2007; DOI 10.1182/blood-2007-08-109058.

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NEOPLASIA

Brief Report

Intact apoptosis signaling in myeloid leukemia cells determines treatment outcome in childhood AML

Lüder H. Meyer1, Manon Queudeville1, Sarah M. Eckhoff1, Ursula Creutzig2, Dirk Reinhardt3, Leonid Karawajew4, Wolf-Dieter Ludwig4, Karsten Stahnke1, and Klaus-Michael Debatin1

1 Department of Paediatrics and Adolescent Medicine, University of Ulm, Ulm; 2 Paediatric Haematology and Oncology, University of Münster, Münster; 3 Paediatric Haematology and Oncology, Medical School Hannover, Hannover; and 4 Department of Haematology, Oncology and Tumor Immunology, Robert-Roessle-Clinic at the HELIOS Klinikum Berlin, Charité Medical School, Berlin, Germany

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 (CRACdep). Patients with positive CRACdep values (intact signaling) exhibited superior survival compared with CRACdep 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 [ClinicalTrials.gov] .


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