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Blood, 12 November 2009, Vol. 114, No. 20, pp. 4451-4459. Prepublished online as a Blood First Edition Paper on September 16, 2009; DOI 10.1182/blood-2009-07-233346. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-07-233346v1 114/20/4451    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 CrossRef Google Scholar Articles by Volanakis, E. J. Articles by Sherr, C. J. PubMed PubMed Citation Articles by Volanakis, E. J. Articles by Sherr, C. J. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemia Emmanuel J. Volanakis1, Richard T. Williams1, and Charles J. Sherr2,3 Departments of 1 Oncology and 2 Genetics & Tumor Cell Biology, and 3 Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, TN Frequent hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) include aberrant NOTCH signaling and deletion of the CDKN2A locus, which contains 2 closely linked tumor suppressor genes (INK4A and ARF). When bone marrow cells or thymocytes transduced with a vector encoding the constitutively activated intracellular domain of Notch1 (ICN1) are expanded ex vivo under conditions that support T-cell development, cultured progenitors rapidly induce CD4+/CD8+ T-ALLs after infusion into healthy syngeneic mice. Under these conditions, enforced ICN1 expression also drives formation of T-ALLs in unconditioned CD-1 nude mice, bypassing any requirements for thymic maturation. Retention of Arf had relatively modest activity in suppressing the formation of T-ALLs arising from bone marrow–derived ICN1+ progenitors in which the locus is epigenetically silenced, and all resulting Arf +/+ tumors failed to express the p19Arf protein. In striking contrast, retention of Arf in thymocyte-derived ICN1+ donor cells significantly delayed disease onset and suppressed the penetrance of T-ALL. Use of cultured thymocyte-derived donor cells expressing a functionally null Arf-GFP knock-in allele confirmed that ICN1 signaling can induce Arf expression in vivo. Arf activation by ICN1 in T cells thereby provides stage-specific tumor suppression but also a strong selective pressure for deletion of the locus in T-ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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