discovery in T-ALL An IL-7-dependent human leukemia T-cell line as a valuable tool for drug

ABSTRACT 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 IL-7-dependent T-ALL cell line – TAIL7 – that maintains several biological and signaling properties of its parental leukemia cells. TAIL7 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, induces cell activation and cell cycle progression. The signaling events triggered by IL-7 include downregulation of p27 kip1 and hyperphosphorylation of Rb. Stimulation of TAIL7 cells by IL-7 leads to phosphorylation of JAK3, STAT5, Akt/PKB and 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. Since TAIL7 cells seem to be a biological 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 anti-leukemia signaling-inhibitors.