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Blood, 1 January 2008, Vol. 111, No. 1, pp. 328-337. Prepublished online as a Blood First Edition Paper on September 21, 2007; DOI 10.1182/blood-2007-07-101519. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-101519v1 111/1/328    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 Citing Articles via Google Scholar Google Scholar Articles by Herling, M. Articles by Jones, D. Search for Related Content PubMed PubMed Citation Articles by Herling, M. Articles by Jones, D. Related Collections Signal Transduction Immunobiology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia Marco Herling1,2, Kaushali A. Patel1, Michael A. Teitell3, Marina Konopleva4, Farhad Ravandi5, Ryuji Kobayashi6, and Dan Jones1 1 Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston; 2 Department of Medicine I, Cologne University, Cologne, Germany; 3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA); 4 Department of Stem Cell Transplantation and Cellular Therapy, 5 Department of Leukemia, and 6 Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston The T-cell leukemia 1 (TCL1) oncoprotein is overexpressed by chromosomal rearrangement in the majority of cases of T-cell prolymphocytic leukemia (T-PLL). In vitro, TCL1 can modulate the activity of the serine-threonine kinase AKT, a downstream effector of T-cell receptor (TCR) signaling. In a series of 86 T-PLL tumors, we show that expression of TCR, and levels of TCL1 and activated AKT are adverse prognostic markers. High-level TCL1 in TCR-expressing T-PLL is associated with higher presenting white blood cell counts, faster tumor cell doubling, and enhanced in vitro growth response to TCR engagement. In primary tumors and TCL1-transfected T-cell lines, TCR engagement leads to rapid recruitment of TCL1 and AKT to transient membrane activation complexes that include TCR-associated tyrosine kinases, including LCK. Pharmacologic inhibition of AKT activation alters the localization, stability, and levels of these transient TCL1-AKT complexes and reduces tumor cell growth. Experimental introduction and knockdown of TCL1 influence the kinetics and strength of TCR-mediated AKT activation. We propose that in T-PLL, TCL1 represents a highly regulated, targetable modulator of TCR-mediated AKT growth signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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