Submitted August 24, 2007
Accepted November 22, 2007
Intact apoptosis signalling in myeloid leukaemia cells determines treatment outcome in childhood AML
Luder Hinrich Meyer, Manon Queudeville, Sarah Mirjam Eckhoff, Ursula Creutzig, Dirk Reinhardt, Leonid Karawajew, Wolf-Dieter Ludwig, Karsten Stahnke, and Klaus-Michael Debatin*
Department of Paediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany
Paediatric Haematology and Oncology, University of Munster, Münster, Germany
Paediatric Haematology and Oncology, Medical School Hannover, Hannover, Germany
Department of Haematology, Oncology and Tumor Immunology, Robert-Roessle-Clinic at the HELIOS Klinikum Berlin, Charite Medical School, Berlin, Germany
* Corresponding author; email: klaus-michael.debatin{at}uniklinik-ulm.de.
Recently we reported that intact apoptosis signalling is indicative of favourable outcome in childhood acute lymphoblastic leukaemia. Here we addressed this issue in 45 paediatric acute myeloid leukaemia patients analysing two core apoptogenic events: cytochrome c release and caspase-3 activation. In patients with good prognosis cytochrome c release was clearly found to be caspase dependent 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 favourable 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 signalling) exhibited superior survival compared to CRACdep -negative patients (deficient signalling). Thus, the propensity to undergo apoptosis of leukaemia cells is an important feature for favourable treatment outcome and may serve as an additional stratification tool for paediatric AML patients. This trial was registered at www.ClinicalTrials.gov as #NCT00111345.
