Asunto(s)
Enfermedades Pulmonares/genética , Linfopenia/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Proteínas de Unión al GTP rac/genética , Adulto , Linfocitos B/inmunología , Progresión de la Enfermedad , Proteínas Activadoras de GTPasa/metabolismo , Mutación con Ganancia de Función , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Guanosina Trifosfato/metabolismo , Trasplante de Células Madre Hematopoyéticas , Heterocigoto , Humanos , Memoria Inmunológica/inmunología , Inmunosupresores/uso terapéutico , Lactante , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón , Linfopenia/inmunología , Masculino , Simulación del Acoplamiento Molecular , Neutrófilos , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/terapia , Recurrencia , Infecciones del Sistema Respiratorio/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Proteínas de Unión al GTP rac/inmunología , Proteínas de Unión al GTP rac/metabolismo , Proteínas de Unión al GTP rac/ultraestructura , Proteína RCA2 de Unión a GTPRESUMEN
Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the ß5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZ-resistant cells revealed upregulation of mutant ß5 subunit of the proteasome. These newly identified ß5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the ß5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant ß5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the α7 subunit of the proteasome can overcome this drug resistance modality.