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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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