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Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng,1*Adolfo A. Ferrando,2*Woojoong Lee,1John P. Morris, IV,2Lewis B. Silverman,2Cheryll Sanchez-Irizarry,1Stephen C. Blacklow,1A. Thomas Look,2Jon C. Aster1
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 normalT cell development. Here, we report that more than 50% of humanT-ALLs, including tumors from all major molecular oncogenicsubtypes, have activating mutations that involve the extracellularheterodimerization domain and/or the C-terminal PEST domainof NOTCH1. These findings greatly expand the role of activatedNOTCH1 in the molecular pathogenesis of human T-ALL and providea strong rationale for targeted therapies that interfere withNOTCH 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.
Present address: Department of Pathology, British Columbia CancerAgency, Vancouver, BC V5Z 4E6, Canada.
To whom correspondence should be addressed. E-mail: jaster{at}rics.bwh.harvard.edu
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Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas.
C. Spaulding, E. J. Reschly, D. E. Zagort, Y. Yashiro-Ohtani, L. J. Beverly, A. Capobianco, W. S. Pear, and B. L. Kee (2007)
Blood
110, 2650-2658
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Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs.
J. Bergeron, E. Clappier, I. Radford, A. Buzyn, C. Millien, G. Soler, P. Ballerini, X. Thomas, J. Soulier, H. Dombret, et al. (2007)
Blood
110, 2324-2330
|Abstract »|Full Text »|PDF »
Notch signaling induces cytoplasmic CD3{epsilon} expression in human differentiating NK cells.
M. De Smedt, T. Taghon, I. Van de Walle, G. De Smet, G. Leclercq, and J. Plum (2007)
Blood
110, 2696-2703
|Abstract »|Full Text »|PDF »
Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group.
S. S. Winter, Z. Jiang, H. M. Khawaja, T. Griffin, M. Devidas, B. L. Asselin, and R. S. Larson (2007)
Blood
110, 1429-1438
|Abstract »|Full Text »|PDF »
The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children.
E. Clappier, W. Cuccuini, A. Kalota, A. Crinquette, J.-M. Cayuela, W. A. Dik, A. W. Langerak, B. Montpellier, B. Nadel, P. Walrafen, et al. (2007)
Blood
110, 1251-1261
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Present address: Department of Pathology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada. 
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