Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Aspergilosis Pulmonar Invasiva/etiología , Leucemia de Células Pilosas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Antiinfecciosos/uso terapéutico , Antineoplásicos/farmacología , Humanos , Indoles/farmacología , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/terapia , Leucemia de Células Pilosas/complicaciones , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Inducción de Remisión , Respiración Artificial , Sulfonamidas/farmacología , VemurafenibRESUMEN
Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in all transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8- and CD3+CD4-CD8- ITK-SYK-positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-gamma. ITK-SYK-positive T-cells showed enhanced apoptosis resistance and INF-gamma production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy.