High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia

Alejandro Gutierrez; Takaomi Sanda; Ruta Grebliunaite; Arkaitz Carracedo; Leonardo Salmena; Yebin Ahn; Suzanne Dahlberg; Donna Neuberg; Lisa A. Moreau; Stuart S. Winter; Richard Larson; Jianhua Zhang; Alexei Protopopov; Lynda Chin; Pier Paolo Pandolfi; Lewis B. Silverman; Stephen P. Hunger; Stephen E. Sallan; A. Thomas Look

doi:10.1182/blood-2009-02-206722

High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia

Alejandro Gutierrez, Takaomi Sanda, Ruta Grebliunaite, Arkaitz Carracedo, Leonardo Salmena, Yebin Ahn, Suzanne Dahlberg, Donna Neuberg, Lisa A. Moreau, Stuart S. Winter, Richard Larson, Jianhua Zhang, Alexei Protopopov, Lynda Chin, Pier Paolo Pandolfi, Lewis B. Silverman, Stephen P. Hunger, Stephen E. Sallan, A. Thomas Look

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

368 Scopus citations

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.

Original language	English (US)
Pages (from-to)	647-650
Number of pages	4
Journal	Blood
Volume	114
Issue number	3
DOIs	https://doi.org/10.1182/blood-2009-02-206722
State	Published - 2009

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Gutierrez, A., Sanda, T., Grebliunaite, R., Carracedo, A., Salmena, L., Ahn, Y., Dahlberg, S., Neuberg, D., Moreau, L. A., Winter, S. S., Larson, R., Zhang, J., Protopopov, A., Chin, L., Pandolfi, P. P., Silverman, L. B., Hunger, S. P., Sallan, S. E., & Look, A. T. (2009). High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood, 114(3), 647-650. https://doi.org/10.1182/blood-2009-02-206722

Gutierrez, A, Sanda, T, Grebliunaite, R, Carracedo, A, Salmena, L, Ahn, Y, Dahlberg, S, Neuberg, D, Moreau, LA, Winter, SS, Larson, R, Zhang, J, Protopopov, A, Chin, L, Pandolfi, PP, Silverman, LB, Hunger, SP, Sallan, SE & Look, AT 2009, 'High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia', Blood, vol. 114, no. 3, pp. 647-650. https://doi.org/10.1182/blood-2009-02-206722

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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.",

author = "Alejandro Gutierrez and Takaomi Sanda and Ruta Grebliunaite and Arkaitz Carracedo and Leonardo Salmena and Yebin Ahn and Suzanne Dahlberg and Donna Neuberg and Moreau, {Lisa A.} and Winter, {Stuart S.} and Richard Larson and Jianhua Zhang and Alexei Protopopov and Lynda Chin and Pandolfi, {Pier Paolo} and Silverman, {Lewis B.} and Hunger, {Stephen P.} and Sallan, {Stephen E.} and Look, {A. Thomas}",

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AU - Carracedo, Arkaitz

AU - Salmena, Leonardo

AU - Ahn, Yebin

AU - Dahlberg, Suzanne

AU - Neuberg, Donna

AU - Moreau, Lisa A.

AU - Winter, Stuart S.

AU - Larson, Richard

AU - Zhang, Jianhua

AU - Protopopov, Alexei

AU - Chin, Lynda

AU - Pandolfi, Pier Paolo

AU - Silverman, Lewis B.

AU - Hunger, Stephen P.

AU - Sallan, Stephen E.

AU - Look, A. Thomas

PY - 2009

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N2 - 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.

AB - 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.

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High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia

Abstract

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