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. 2009 Jul 30;114(5):1053-62.
doi: 10.1182/blood-2008-10-186536. Epub 2009 Apr 30.

High-resolution Genomic Profiling of Childhood T-ALL Reveals Frequent Copy-Number Alterations Affecting the TGF-beta and PI3K-AKT Pathways and Deletions at 6q15-16.1 as a Genomic Marker for Unfavorable Early Treatment Response

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High-resolution Genomic Profiling of Childhood T-ALL Reveals Frequent Copy-Number Alterations Affecting the TGF-beta and PI3K-AKT Pathways and Deletions at 6q15-16.1 as a Genomic Marker for Unfavorable Early Treatment Response

Marc Remke et al. Blood. .

Abstract

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-beta 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-beta and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response.

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