IL-7-dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL.
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 p27(kip1) 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.
Barata
Joao T
JT
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Boussiotis
Vassiliki A
VA
Yunes
Jose A
JA
Ferrando
Adolfo A
AA
Moreau
Lisa A
LA
Veiga
J Pedro
JP
Sallan
Stephen E
SE
Look
A Thomas
AT
Nadler
Lee M
LM
Cardoso
Angelo A
AA
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D053616:Janus Kinase 3; D007621:Karyotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D015851:Interleukin-7; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015847:Interleukin-4; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases