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

作者：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^*

来源：Blood, 2009, 114(5): 1053-1062.

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-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. (Blood. 2009; 114: 1053-1062)

• 出版日期2009-7-30