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Blood, 1 August 2008, Vol. 112, No. 3, pp. 733-740. Prepublished online as a Blood First Edition Paper on April 14, 2008; DOI 10.1182/blood-2007-12-130096. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-12-130096v1 112/3/733    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sulis, M. L. Articles by Ferrando, A. A. Search for Related Content PubMed PubMed Citation Articles by Sulis, M. L. Articles by Ferrando, A. A. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL Maria Luisa Sulis1,2, Odette Williams2, Teresa Palomero2,3, Valeria Tosello2, Sasikala Pallikuppam2, Pedro J. Real2, Kelly Barnes2, Linda Zuurbier4, Jules P. Meijerink4, and Adolfo A. Ferrando13 1 Division of Pediatric Oncology, Department of Pediatrics; 2 Institute for Cancer Genetics; and 3 Department of Pathology, Columbia University Medical Center, New York, NY; and 4 Department of Pediatric Oncology/Hematology, Erasmus Medical Center (MC) Sophia Children's Hospital, Rotterdam, The Netherlands Heterodimerization domain (HD) mutations in NOTCH1 induce ligand-independent activation of the receptor and contribute to the pathogenesis of one-third of human T-cell lymphoblastic leukemias (T-ALLs). Here we report a novel class of activating mutations in NOTCH1 leading to aberrant activation of NOTCH1 signaling in T-cell lymphoblasts. These so-called juxtamembrane expansion (JME) alleles consist of internal duplication insertions in the vicinity of exon 28 of the NOTCH1 gene encoding the extracellular juxtamembrane region of the receptor. Notably, structure-function analysis of leukemia-derived and synthetic JME mutants demonstrated that the aberrant activation of NOTCH1 signaling is dependent on the number of residues introduced in the extracellular juxtamembrane region of the receptor and not on the specific amino acid sequence of these insertions. JME NOTCH1 mutants are effectively blocked by -secretase inhibitors and require an intact metalloprotease cleavage site for activation. Overall, these results show a novel mechanism of NOTCH1 activation in T-ALL and provide further insight on the mechanisms that control the activation of NOTCH1 signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fifty ways to Notch T-ALL Marei Dose and Fotini Gounari Blood 2008 112: 457-458. [Full Text] [PDF] This article has been cited by other articles: K. Cullion, K. M. Draheim, N. Hermance, J. Tammam, V. M. Sharma, C. Ware, G. Nikov, V. Krishnamoorthy, P. K. Majumder, and M. A. Kelliher Targeting the Notch1 and mTOR pathways in a mouse T-ALL model Blood, June 11, 2009; 113(24): 6172 - 6181. [Abstract] [Full Text] [PDF] W. R. Gordon, M. Roy, D. Vardar-Ulu, M. Garfinkel, M. R. Mansour, J. C. Aster, and S. C. Blacklow Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL Blood, April 30, 2009; 113(18): 4381 - 4390. [Abstract] [Full Text] [PDF] V. Asnafi, A. Buzyn, S. Le Noir, F. Baleydier, A. Simon, K. Beldjord, O. Reman, F. Witz, T. Fagot, E. Tavernier, et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study Blood, April 23, 2009; 113(17): 3918 - 3924. [Abstract] [Full Text] [PDF]

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