title: 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.
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.
authors.affiliation: German Cancer Research Center (DKFZ), Division Molecular Genetics, Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Corinne
authors.initials: C
authors.lastname: Kox
authors.forename: Grischa
authors.initials: G
authors.lastname: Toedt
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Wiebke
authors.initials: W
authors.lastname: Werft
authors.forename: Stephen
authors.initials: S
authors.lastname: Breit
authors.forename: Shuangyou
authors.initials: S
authors.lastname: Liu
authors.forename: Felix
authors.initials: F
authors.lastname: Engel
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics* / Q000648:ultrastructure; D055028:Comparative Genomic Hybridization; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D018628:Gene Dosage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009363:Neoplasm Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt