Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

A. Gutierrez; R. Grebliunaite; H. Feng; E. Kozakewich; S. Zhu; F. Guo; E. Payne; M. Mansour; S.E. Dahlberg; D.S. Neuberg; J. den Hertog; E.V. Prochownik; J.R. Testa; M. Harris; J.P. Kanki; A.T. Look

doi:10.1084/jem.20101691

Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

A. Gutierrez, R. Grebliunaite, H. Feng, E. Kozakewich, S. Zhu, F. Guo, E. Payne, M. Mansour, S.E. Dahlberg, D.S. Neuberg, J. den Hertog, E.V. Prochownik, J.R. Testa, M. Harris, J.P. Kanki, A.T. Look

Hubrecht Institute

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Abstract

The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

Original language	English
Pages (from-to)	1595-1603
Journal	Journal of Experimental Medicine
Volume	208
Issue number	8
DOIs	https://doi.org/10.1084/jem.20101691
Publication status	Published - 2011

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Gutierrez, A., Grebliunaite, R., Feng, H., Kozakewich, E., Zhu, S., Guo, F., Payne, E., Mansour, M., Dahlberg, S. E., Neuberg, D. S., den Hertog, J., Prochownik, E. V., Testa, J. R., Harris, M., Kanki, J. P., & Look, A. T. (2011). Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. Journal of Experimental Medicine, 208(8), 1595-1603. https://doi.org/10.1084/jem.20101691

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title = "Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia",

abstract = "The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.",

author = "A. Gutierrez and R. Grebliunaite and H. Feng and E. Kozakewich and S. Zhu and F. Guo and E. Payne and M. Mansour and S.E. Dahlberg and D.S. Neuberg and {den Hertog}, J. and E.V. Prochownik and J.R. Testa and M. Harris and J.P. Kanki and A.T. Look",

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doi = "10.1084/jem.20101691",

language = "English",

volume = "208",

pages = "1595--1603",

journal = "Journal of Experimental Medicine",

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Gutierrez, A, Grebliunaite, R, Feng, H, Kozakewich, E, Zhu, S, Guo, F, Payne, E, Mansour, M, Dahlberg, SE, Neuberg, DS, den Hertog, J, Prochownik, EV, Testa, JR, Harris, M, Kanki, JP & Look, AT 2011, 'Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia', Journal of Experimental Medicine, vol. 208, no. 8, pp. 1595-1603. https://doi.org/10.1084/jem.20101691

TY - JOUR

T1 - Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

AU - Gutierrez, A.

AU - Grebliunaite, R.

AU - Feng, H.

AU - Kozakewich, E.

AU - Zhu, S.

AU - Guo, F.

AU - Payne, E.

AU - Mansour, M.

AU - Dahlberg, S.E.

AU - Neuberg, D.S.

AU - den Hertog, J.

AU - Prochownik, E.V.

AU - Testa, J.R.

AU - Harris, M.

AU - Kanki, J.P.

AU - Look, A.T.

N1 - Reporting year: 2011

PY - 2011

Y1 - 2011

N2 - The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

AB - The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN-PI3K-AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC promotes tumor progression. Our findings indicate that Akt pathway activation is sufficient for tumor maintenance in this model, even after loss of survival signals driven by the MYC oncogene.

U2 - 10.1084/jem.20101691

DO - 10.1084/jem.20101691

M3 - Article

SN - 0022-1007

VL - 208

SP - 1595

EP - 1603

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 8

ER -

Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia

Abstract

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