Genomische Charakterisierung der T-ALL mit Hilfe der Mikroarray-comparative genomic Hybridisierung (Array-CGH)

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Acute lymphoblastic leukemia (ALL) is the most common cancer in children, accounting for almost % of all cancer diagnoses in children under the age of 15. Since little is known about the causes and risk factors for childhood ALL, successful treatment of pediatric ALL weighs heavily on accurate assessment of the patient s disease subtype, determined by genetic rearrangements and alterations. Chromosomal analysis (cytogenetics) is one means by which leukemias are routinely subtyped. Unfortunately, conventional cytogenetic methods have limited resolution while higher-resolution methods only interrogate known genomic aberrations. Thus, it is believed that many of the genetic defects underlying ALL escape detection via conventional cytogenetic methodologies. In this proposal, we plan on using state-of-the-art genetic technologies, array-based comparative genomic hybridization (array-CGH) and multicolor molecular cytogenetic technologies to identify genomic imbalances that occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL), the more aggressive form of childhood ALL. Array-CGH is an emerging technology for high-resolution and highthroughput screening of cancer cells for chromosomal imbalances. In a pilot study on CLL, our laboratory has already demonstrated that array-CGH can detect all known chromosomal imbalances, as well as identify novel, recurrent and prognostically-informative genomic markers. Similarly, we believe that array- CGH studies will yield informative biomarkers in T-ALL that will help us to identify patients with more aggressive subtypes of T-ALL (who would be candidates for more aggressive and earlier institution of therapy). Moreover, the identification of dysregulated genes associated with T-ALL could provide insights into the molecular mechanisms of white blood cell malignancies. The proposed studies will (1) Identify and characterize large-scale copy number variations in the human genome for accurate array-CGH profiling, (2) Identify new genetic markers for TALL diagnosis, and (3) Investigate the genomic changes that occur in T-ALL after therapy and at relapse.