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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1891-1900.
Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2002-12-3861.
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NEOPLASIA
IL-7–dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL
Joao T. Barata,
Vassiliki A. Boussiotis,
Jose A. Yunes,
Adolfo A. Ferrando,
Lisa A. Moreau,
J. Pedro Veiga,
Stephen E. Sallan,
A. Thomas Look,
Lee M. Nadler, and
Angelo A. Cardoso
From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Unit of Tumor Biology, Institute of Molecular Medicine, University of Lisbon Medical School, Lisbon, Portugal.
The specific targeting of critical signaling molecules may provide efficient therapies for T-cell acute lymphoblastic leukemia (T-ALL). However, target identification and drug development are limited by insufficient numbers of primary T-ALL cells and by their high rate of spontaneous apoptosis. We established a human interleukin-7 (IL-7)–dependent T-ALL cell line, TAIL7, that maintains several biologic and signaling properties of its parental leukemia cells. TAIL7 cells are pre–T-ALL cells that proliferate in response to IL-7 and IL-4. IL-7 stimulation of TAIL7 cells prevents spontaneous in vitro apoptosis and induces cell activation and cell cycle progression. The signaling events triggered by IL-7 include down-regulation of p27kip1 and hyperphosphorylation of retinoblastoma protein (Rb). Stimulation of TAIL7 cells by IL-7 leads to phosphorylation of Janus kinase 3 (JAK3), signal transducer and activator of transcription 5 (STAT5), Akt/PKB (protein kinase B), and extracellular-regulated kinase 1 and 2 (Erk1/2). Importantly, specific blockade of JAK3 by its inhibitor WHI-P131 abrogates the IL-7–mediated proliferation and survival of TAIL7 cells, suggesting that activation of JAK3 is critical for IL-7 responsiveness by these cells. Because TAIL7 cells seem to be a biologic surrogate for primary leukemia T cells, this cell line constitutes a valuable tool for the study of the signaling pathways implicated in T-ALL. Exploitation of this cell line should allow the identification of molecular targets and promote the rational design and validation of antileukemia signaling inhibitors.
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