RESUMO
Understanding the pathogenesis of leukemia in the context of lymphopoiesis may reveal novel therapeutic targets. Previously, we have shown that mTOR inhibitors (MTI) show activity in vitro and in preclinical models of both human and murine precursor B acute lymphoblastic leukemia (pre-B ALL), inhibiting cell proliferation and inducing apoptosis. These MTI-mediated effects can be reversed by interleukin-7 (IL-7), an important regulator of early B-cell development. This observation led us to examine the contribution of signaling via the IL-7Ralpha chain, which is shared by the receptor complexes of IL-7 and thymic stromal-derived lymphopoietin (TSLP). TSLP is closely related to IL-7 and active in lymphopoiesis, but an effect of TSLP on leukemia cells has not been described. We examined the effect of TSLP on pre-B ALL cells and their response to MTIs. Here, we show that TSLP stimulates proliferation of pre-B ALL cell lines. TSLP also partially reverses the effects of MTI on proliferation, apoptosis, and ribosomal protein S6 and 4E-BP1 phosphorylation in cell lines, with similar biological effects seen in some primary human lymphoblast samples. These data show that TSLP can promote survival of pre-B ALL cells and antagonize the effects of MTIs. These findings suggest that IL-7Ralpha chain is responsible for transducing the survival signal that overcomes MTI-mediated growth inhibition in pre-B ALL. Thus, further exploration of the IL-7Ralpha pathway may identify potential therapeutic targets in the treatment of ALL. Our data illustrate that growth-factor-mediated signaling may provide one mechanism of MTI resistance.
Assuntos
Citocinas/farmacologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Citocinas/antagonistas & inibidores , Interações Medicamentosas , Fatores de Iniciação em Eucariotos , Humanos , Interleucina-7/antagonistas & inibidores , Interleucina-7/metabolismo , Interleucina-7/farmacologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Janus Quinase 1/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Camundongos Transgênicos , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Inibidores de Proteínas Quinases/antagonistas & inibidores , Proteínas Recombinantes/farmacologia , Proteína S6 Ribossômica/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Linfopoietina do Estroma do TimoRESUMO
Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti-double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.