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Science 306 (5694): 269-271

Copyright © 2004 by the American Association for the Advancement of Science

Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia

Andrew P. Weng,1*{dagger} Adolfo A. Ferrando,2* Woojoong Lee,1 John P. Morris, IV,2 Lewis B. Silverman,2 Cheryll Sanchez-Irizarry,1 Stephen C. Blacklow,1 A. Thomas Look,2 Jon C. Aster1{ddagger}

Abstract: Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

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* These authors contributed equally to this work.

{dagger} Present address: Department of Pathology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada.

{ddagger} To whom correspondence should be addressed. E-mail: jaster{at}rics.bwh.harvard.edu

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M. Bonnet, M. Loosveld, B. Montpellier, J.-M. Navarro, B. Quilichini, C. Picard, J. Di Cristofaro, C. Bagnis, C. Fossat, L. Hernandez, et al. (2011)
Blood 117, 6650-6659
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Functional interactions between Lmo2, the Arf tumor suppressor, and Notch1 in murine T-cell malignancies.
L. M. Treanor, E. J. Volanakis, S. Zhou, T. Lu, C. J. Sherr, and B. P. Sorrentino (2011)
Blood 117, 5453-5462
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MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context.
M. Kleppe, N. Mentens, T. Tousseyn, I. Wlodarska, and J. Cools (2011)
Haematologica 96, 779-783
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Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.
E. Clappier, B. Gerby, F. Sigaux, M. Delord, F. Touzri, L. Hernandez, P. Ballerini, A. Baruchel, F. Pflumio, and J. Soulier (2011)
J. Exp. Med. 208, 653-661
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Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL.
X. Li, T. Sanda, A. T. Look, C. D. Novina, and H. von Boehmer (2011)
J. Exp. Med. 208, 663-675
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