This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sharma, V. M.
Right arrow Articles by Kelliher, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sharma, V. M.
Right arrow Articles by Kelliher, M. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2006, p. 8022-8031, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01091-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc{triangledown}

Vishva Mitra Sharma,1,§ Jennifer A. Calvo,1,§,{ddagger} Kyle M. Draheim,1 Leslie A. Cunningham,1 Nicole Hermance,1 Levi Beverly,2 Veena Krishnamoorthy,1 Manoj Bhasin,3 Anthony J. Capobianco,2 and Michelle A. Kelliher1*

Department of Cancer Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts,1 Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts,3 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania2

Received 16 June 2006/ Returned for modification 17 July 2006/ Accepted 8 August 2006

Recent work with mouse models and human leukemic samples has shown that gain-of-function mutation(s) in Notch1 is a common genetic event in T-cell acute lymphoblastic leukemia (T-ALL). The Notch1 receptor signals through a {gamma}-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus, where it forms part of a transcriptional activator complex. To identify Notch1 target genes in leukemia, we developed mouse T-cell leukemic lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel, direct, and critical Notch1 target gene in T-cell leukemia. c-myc mRNA levels are increased in primary mouse T-cell tumors that harbor Notch1 mutations, and Notch1 inhibition decreases c-myc mRNA levels and inhibits leukemic cell growth. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with {gamma}-secretase inhibitor treatment or Notch1 inhibition. Consistent with these findings, retroviral insertional mutagenesis screening of our T-cell leukemia mouse model revealed common insertions in either notch1 or c-myc genes. These studies define the Notch1 molecular signature in mouse T-ALL and importantly provide mechanistic insight as to how Notch1 contributes to human T-ALL.

* Corresponding author. Mailing address: Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Phone: (508) 856-8620. Fax: (508) 856-1310. E-mail: michelle.kelliher{at}umassmed.edu.

{triangledown} Published ahead of print on 5 September 2006.

§ V.M.S. and J.A.C. contributed equally to this work.

{ddagger} Present address: Diabetes Division, Novartis, Inc., Cambridge, MA 02139.

Molecular and Cellular Biology, November 2006, p. 8022-8031, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01091-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Finch, A. J., Soucek, L., Junttila, M. R., Swigart, L. B., Evan, G. I. (2009). Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/{beta}-Catenin Pathway Activation. Mol. Cell. Biol. 29: 5306-5315 [Abstract] [Full Text]  
  • FU, L., KATSUBE, K.-I., TOHDA, S. (2009). Transition of Cleaved Notch1 and Gene Expression Changes in Myeloblastic Leukemia Cells Stimulated with Notch Ligands. Anticancer Res 29: 3967-3970 [Abstract] [Full Text]  
  • Cullion, K., Draheim, K. M., Hermance, N., Tammam, J., Sharma, V. M., Ware, C., Nikov, G., Krishnamoorthy, V., Majumder, P. K., Kelliher, M. A. (2009). Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 113: 6172-6181 [Abstract] [Full Text]  
  • Kohlhof, H., Hampel, F., Hoffmann, R., Burtscher, H., Weidle, U. H., Holzel, M., Eick, D., Zimber-Strobl, U., Strobl, L. J. (2009). Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus-infected B cells. Blood 113: 5506-5515 [Abstract] [Full Text]  
  • Bertout, J. A., Patel, S. A., Fryer, B. H., Durham, A. C., Covello, K. L., Olive, K. P., Goldschmidt, M. H., Simon, M. C. (2009). Heterozygosity for Hypoxia Inducible Factor 1{alpha} Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model. Cancer Res. 69: 3213-3220 [Abstract] [Full Text]  
  • Rao, S. S., O'Neil, J., Liberator, C. D., Hardwick, J. S., Dai, X., Zhang, T., Tyminski, E., Yuan, J., Kohl, N. E., Richon, V. M., Van der Ploeg, L. H.T., Carroll, P. M., Draetta, G. F., Look, A. T., Strack, P. R., Winter, C. G. (2009). Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells. Cancer Res. 69: 3060-3068 [Abstract] [Full Text]  
  • Palomero, T., Ferrando, A. (2008). Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas. Clin. Cancer Res. 14: 5314-5317 [Abstract] [Full Text]  
  • Hsu, K.-W., Hsieh, R.-H., Lee, Y.-H. W., Chao, C.-H., Wu, K.-J., Tseng, M.-J., Yeh, T.-S. (2008). The Activated Notch1 Receptor Cooperates with {alpha}-Enolase and MBP-1 in Modulating c-myc Activity. Mol. Cell. Biol. 28: 4829-4842 [Abstract] [Full Text]  
  • Lee, C. W., Raskett, C. M., Prudovsky, I., Altieri, D. C. (2008). Molecular Dependence of Estrogen Receptor-Negative Breast Cancer on a Notch-Survivin Signaling Axis. Cancer Res. 68: 5273-5281 [Abstract] [Full Text]  
  • Van Vlierberghe, P., van Grotel, M., Tchinda, J., Lee, C., Beverloo, H. B., van der Spek, P. J., Stubbs, A., Cools, J., Nagata, K., Fornerod, M., Buijs-Gladdines, J., Horstmann, M., van Wering, E. R., Soulier, J., Pieters, R., Meijerink, J. P. P. (2008). The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 111: 4668-4680 [Abstract] [Full Text]  
  • De Keersmaecker, K., Lahortiga, I., Mentens, N., Folens, C., Van Neste, L., Bekaert, S., Vandenberghe, P., Odero, M. D., Marynen, P., Cools, J. (2008). In vitro validation of {gamma}-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. haematol 93: 533-542 [Abstract] [Full Text]  
  • Wang, S.-F., Aoki, M., Nakashima, Y., Shinozuka, Y., Tanaka, H., Taniwaki, M., Hattori, M., Minato, N. (2008). Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling. Blood 111: 2878-2886 [Abstract] [Full Text]  
  • O'Neil, J., Tchinda, J., Gutierrez, A., Moreau, L., Maser, R. S., Wong, K.-K., Li, W., McKenna, K., Liu, X. S., Feng, B., Neuberg, D., Silverman, L., DeAngelo, D. J., Kutok, J. L., Rothstein, R., DePinho, R. A., Chin, L., Lee, C., Look, A. T. (2007). Alu elements mediate MYB gene tandem duplication in human T-ALL. JEM 204: 3059-3066 [Abstract] [Full Text]  
  • Mansour, M. R., Duke, V., Foroni, L., Patel, B., Allen, C. G., Ancliff, P. J., Gale, R. E., Linch, D. C. (2007). Notch-1 Mutations Are Secondary Events in Some Patients with T-Cell Acute Lymphoblastic Leukemia. Clin. Cancer Res. 13: 6964-6969 [Abstract] [Full Text]  
  • Liao, W.-R., Hsieh, R.-H., Hsu, K.-W., Wu, M.-Z., Tseng, M.-J., Mai, R.-T., Wu Lee, Y.-H., Yeh, T.-S. (2007). The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. Carcinogenesis 28: 1867-1876 [Abstract] [Full Text]  
  • Thompson, B. J., Buonamici, S., Sulis, M. L., Palomero, T., Vilimas, T., Basso, G., Ferrando, A., Aifantis, I. (2007). The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. JEM 204: 1825-1835 [Abstract] [Full Text]  
  • O'Neil, J., Grim, J., Strack, P., Rao, S., Tibbitts, D., Winter, C., Hardwick, J., Welcker, M., Meijerink, J. P., Pieters, R., Draetta, G., Sears, R., Clurman, B. E., Look, A. T. (2007). FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors. JEM 204: 1813-1824 [Abstract] [Full Text]  
  • Chan, S. M., Weng, A. P., Tibshirani, R., Aster, J. C., Utz, P. J. (2007). Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 110: 278-286 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»