AbstractBackgroundRisk-adjusted treatment has led to outstanding improvements of the remission and survival rates of childhood acute lymphoblastic leukemia (ALL). Nevertheless, overtreatment-related toxicity and resistance to therapy have not been fully prevented. In the present study, we evaluated for the first time the clinical impact of the apoptosis-relatedBCL2L12gene in prognosis and risk stratification of BFM-treated childhood ALL.MethodsBone marrow specimens were obtained from childhood ALL patients upon disease diagnosis and the end-of-induction (EoI; day 33) of the BFM protocol, as well as from control children. Following total RNA extraction and reverse transcription,BCL2L12expression levels were determined by qPCR. Patients’ cytogenetics, immunophenotyping and minimal residual disease (MRD) evaluation were performed according to the international guidelines.ResultsBCL2L12expression was significantly increased in childhood ALL and correlated with higherBCL2/BAXexpression ratio and favorable disease markers. More importantly,BCL2L12expression was associated with disease remission, while the reducedBCL2L12expression was able to predict patients’ poor response to BFM therapy, in terms of M2-M3 response and MRD≥0.1% on day 15. The survival analysis confirmed the significantly higher risk of the BFM-treated patients underexpressingBCL2L12at disease diagnosis for early relapse and worse survival. Lastly, evaluation ofBCL2L12expression clearly strengthened the prognostic value of the established disease prognostic markers, leading to superior prediction of patients’ outcome and improved specificity of BFM risk stratification.ConclusionsThe expression levels of the apoptosis-relatedBCL2L12predict response to treatment and survival outcome of childhood ALL patients receiving BFM chemotherapy.