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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 20, 2007 Accepted March 18, 2008 NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL Maria Luisa Sulis, Odette Williams, Teresa Palomero, Valeria Tosello, Sasikala Pallikuppam, Pedro J Real, Kelly Barnes, Linda Zuurbier, Jules P. Meijerink, and Adolfo A. Ferrando* Pediatric Oncology Division, Department of Pediatrics, Columbia University, New york, NY, United States Institute for Cancer Genetics, Columbia University, New York, NY, United States Department of Pathology, Columbia University, New York, NY, United States Department of Pediatric Oncology/Hematology, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands * Corresponding author; email: af2196{at}columbia.edu. 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-ALL). 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: E. C. Bozkulak and G. Weinmaster Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling Mol. Cell. Biol., November 1, 2009; 29(21): 5679 - 5695. [Abstract] [Full Text] [PDF] D. K. Finlay, L. V. Sinclair, C. Feijoo, C. M. Waugh, T. J. Hagenbeek, H. Spits, and D. A. Cantrell Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes J. Exp. Med., October 26, 2009; 206(11): 2441 - 2454. [Abstract] [Full Text] [PDF] C. D. Baldus, J. Thibaut, N. Goekbuget, A. Stroux, C. Schlee, M. Mossner, T. Burmeister, S. Schwartz, C. D. Bloomfield, D. Hoelzer, et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia Haematologica, October 1, 2009; 94(10): 1383 - 1390. [Abstract] [Full Text] [PDF] M. R. Mansour, M. L. Sulis, V. Duke, L. Foroni, S. Jenkinson, K. Koo, C. G. Allen, R. E. Gale, G. Buck, S. Richards, et al. Prognostic Implications of NOTCH1 and FBXW7 Mutations in Adults With T-Cell Acute Lymphoblastic Leukemia Treated on the MRC UKALLXII/ECOG E2993 Protocol J. Clin. Oncol., September 10, 2009; 27(26): 4352 - 4356. [Abstract] [Full Text] [PDF] V. Tosello, M. R. Mansour, K. Barnes, M. Paganin, M. L. Sulis, S. Jenkinson, C. G. Allen, R. E. Gale, D. C. Linch, T. Palomero, et al. WT1 mutations in T-ALL Blood, July 30, 2009; 114(5): 1038 - 1045. [Abstract] [Full Text] [PDF] 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] T. Palomero and A. Ferrando Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas Clin. Cancer Res., September 1, 2008; 14(17): 5314 - 5317. [Abstract] [Full Text] [PDF]

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