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Molecular and Cellular Biology, January 2003, p. 655-664, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.655-664.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling

Andrew P. Weng,1,2 Yunsun Nam,1,2 Michael S. Wolfe,3 Warren S. Pear,4 James D. Griffin,3,5 Stephen C. Blacklow,1,2 and Jon C. Aster1,2*

Departments of Pathology,1 Medicine, Brigham Women's Hospital,3 Department of Pathology, Harvard Medical School,2 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115,5 Department of Pathology and Laboratory Medicine, Institute for Medicine and Engineering, The Abramson Family Cancer Research Institute, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 191044

Received 26 July 2002/ Returned for modification 20 September 2002/ Accepted 21 October 2002

Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.

* Corresponding author. Mailing address: Brigham and Women's Hospital, Department of Pathology, 20 Shattuck St./Thorn 503, Boston, MA 02115. Phone: (617) 732-7980. Fax: (617) 732-7449. E-mail: jaster{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, January 2003, p. 655-664, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.655-664.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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