High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response

• Published in: Blood 2009-07, Vol.114 (5), p.1053-1062
• Main Authors: Remke, Marc, Pfister, Stefan, Kox, Corinne, Toedt, Grischa, Becker, Natalia, Benner, Axel, Werft, Wiebke, Breit, Stephen, Liu, Shuangyou, Engel, Felix, Wittmann, Andrea, Zimmermann, Martin, Stanulla, Martin, Schrappe, Martin, Ludwig, Wolf-Dieter, Bartram, Claus R., Radlwimmer, Bernhard, Muckenthaler, Martina U., Lichter, Peter, Kulozik, Andreas E.
• Format: Article
• Language: English
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 6 - genetics; Chromosomes, Human, Pair 6 - ultrastructure; Comparative Genomic Hybridization; Cyclin-Dependent Kinase Inhibitor p27; Female; Gene Dosage; Humans; Intracellular Signaling Peptides and Proteins - genetics; Male; Multicenter Studies as Topic - statistics & numerical data; Neoplasm Proteins - genetics; Phosphatidylinositol 3-Kinases - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - mortality; Prognosis; Proto-Oncogene Proteins c-akt - genetics; Receptor, Notch1 - genetics; Signal Transduction - genetics; Transforming Growth Factor beta - genetics; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-10-186536

Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents a clinical challenge, because relapses are usually fatal. It is thus necessary to identify high-risk patients as early as possible to effectively individualize treatment. We aimed to define novel molecular risk markers in T-ALL and performed array-based comparative genomic hybridization (array-CGH) and expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL and affect 70 of 73 (96%) patients. Notably, genomic imbalances predicted to down-regulate the TGF-β or up-regulate the PI3K-AKT pathways are identified in 25 of 73 (34%) and 21 of 73 (29%) patients, suggesting that these pathways play key roles in T-ALL leukemogenesis. Furthermore, we identified a deletion at 6q15-16.1 in 9 of 73 (12%) of the patients, which predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. The interaction of CASP8AP2 with CASP8 plays a crucial role in apoptotic regulation, suggesting a functional link between the clinical effect of the deletion and the molecular mode of action. The data presented here implicate the TGF-β and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response.