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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.



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