title: High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia.
abstract: To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.forename: Ruta
authors.initials: R
authors.lastname: Grebliunaite
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Yebin
authors.initials: Y
authors.lastname: Ahn
authors.forename: Suzanne
authors.initials: S
authors.lastname: Dahlberg
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Moreau
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Winter
authors.forename: Richard
authors.initials: R
authors.lastname: Larson
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D002648:Child; D055028:Comparative Genomic Hybridization; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human