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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2878-2886. Prepublished online as a Blood First Edition Paper on January 7, 2008; DOI 10.1182/blood-2007-07-103119. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-103119v1 111/5/2878    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 Wang, S.-F. Articles by Minato, N. Search for Related Content PubMed PubMed Citation Articles by Wang, S.-F. Articles by Minato, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 24, 2007 Accepted December 24, 2007 Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling Shu-Fang Wang, Misayo Aoki, Yasuhiro Nakashima, Yoriko Shinozuka, Hiroki Tanaka, Masafumi Taniwaki, Masakazu Hattori, and Nagahiro Minato* Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan Graduate School of Medicine, Kyoto University, Kyoto, Japan Department of Hematology and Oncology, Kyoto Prefectural School of Medicine, Kyoto, Japan * Corresponding author; email: minato{at}imm.med.kyoto-u.ac.jp. SPA-1 (signal-induced proliferation associated gene-1) functions as a suppressor of myeloid leukemia by negatively regulating Rap1 signaling in hematopoietic progenitor cells (HPC). Herein, we showed that transplantation of HPC expressing farnesylated C3G (C3G-F), a Rap1 guanine nucleotide exchange factor, resulted in a marked expansion of thymocytes bearing unique phenotypes (CD4/CD8 double positive [DP] CD3- TCR-) in irradiated recipients. SPA-1-/- HPC expressing C3G-F caused a more extensive expansion of DP thymocytes, resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL) with massive invasion of clonal T-cell blasts into vital organs. The C3G-F+ blastic thymocytes exhibited constitutive Rap1 activation and markedly enhanced expression of Notch1, 3 as well as the target genes, Hes1, pT, and c-Myc. All the T-ALL cell lines from C3G-F+ SPA-1-/- HPC recipients expressed high levels of Notch1 with characteristic mutations resulting in the C-terminal truncation. This proliferation was inhibited completely in the presence of a -secretase inhibitor. Transplantation of Rag2-/- SPA-1-/- HPC expressing C3G-F also resulted in a marked expansion and transformation of DP thymocytes. The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Katayama, M. Sekai, M. Hattori, I. Miyoshi, Y. Hamazaki, and N. Minato Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells Blood, August 27, 2009; 114(9): 1768 - 1775. [Abstract] [Full Text] [PDF] K. Kometani, M. Moriyama, Y. Nakashima, Y. Katayama, S.-F. Wang, S. Yamasaki, T. Saito, M. Hattori, and N. Minato Essential role of Rap signal in pre-TCR-mediated {beta}-selection checkpoint in {alpha}{beta} T-cell development Blood, December 1, 2008; 112(12): 4565 - 4573. [Abstract] [Full Text] [PDF]

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