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Science 8 October 2004:
Vol. 306. no. 5694, pp. 269 - 271
DOI: 10.1126/science.1102160
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Reports

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}

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.



* 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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   Abstract »    Full Text »    PDF »
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors.
J. O'Neil, J. Grim, P. Strack, S. Rao, D. Tibbitts, C. Winter, J. Hardwick, M. Welcker, J. P. Meijerink, R. Pieters, et al. (2007)
J. Exp. Med. 204, 1813-1824
   Abstract »    Full Text »    PDF »
Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors.
A. Fischer and M. Gessler (2007)
Nucleic Acids Res. 35, 4583-4596
   Abstract »    Full Text »    PDF »
Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.
S. M. Chan, A. P. Weng, R. Tibshirani, J. C. Aster, and P. J. Utz (2007)
Blood 110, 278-286
   Abstract »    Full Text »    PDF »
The Tumor Suppressor Gene hCDC4 Is Frequently Mutated in Human T-Cell Acute Lymphoblastic Leukemia with Functional Consequences for Notch Signaling.
A. Malyukova, T. Dohda, N. von der Lehr, S. Akhondi, M. Corcoran, M. Heyman, C. Spruck, D. Grander, U. Lendahl, and O. Sangfelt (2007)
Cancer Res. 67, 5611-5616
   Abstract »    Full Text »    PDF »
{beta}-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation.
Z. Guo, M. Dose, D. Kovalovsky, R. Chang, J. O'Neil, A. T. Look, H. von Boehmer, K. Khazaie, and F. Gounari (2007)
Blood 109, 5463-5472
   Abstract »    Full Text »    PDF »
Delta-Like 4 Induces Notch Signaling in Macrophages: Implications for Inflammation.
E. Fung, S.-M. T. Tang, J. P. Canner, K. Morishige, J. F. Arboleda-Velasquez, A. A. Cardoso, N. Carlesso, J. C. Aster, and M. Aikawa (2007)
Circulation 115, 2948-2956
   Abstract »    Full Text »    PDF »
Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo.
T. Oyama, K. Harigaya, A. Muradil, K. Hozumi, S. Habu, H. Oguro, A. Iwama, K. Matsuno, R. Sakamoto, M. Sato, et al. (2007)
PNAS 104, 9764-9769
   Abstract »    Full Text »    PDF »
Regulation of Notch1 Gene Expression by p53 in Epithelial Cells.
T. Yugawa, K. Handa, M. Narisawa-Saito, S.-i. Ohno, M. Fujita, and T. Kiyono (2007)
Mol. Cell. Biol. 27, 3732-3742
   Abstract »    Full Text »    PDF »
Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF.
T. Maeda, T. Merghoub, R. M. Hobbs, L. Dong, M. Maeda, J. Zakrzewski, M. R.M. van den Brink, A. Zelent, H. Shigematsu, K. Akashi, et al. (2007)
Science 316, 860-866
   Abstract »    Full Text »    PDF »
Notch Signaling in Development and Cancer.
V. Bolos, J. Grego-Bessa, and J. L. de la Pompa (2007)
Endocr. Rev. 28, 339-363
   Abstract »    Full Text »    PDF »


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