Asunto(s)
Células de la Médula Ósea/patología , Hematopoyesis/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/patología , Mieloma Múltiple/patología , Factores de Edad , Anciano , Linfocitos B/inmunología , Linfocitos B/patología , Células de la Médula Ósea/inmunología , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hematopoyesis/inmunología , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma Folicular/genética , Linfoma Folicular/inmunología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunologíaRESUMEN
PURPOSE: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGNS: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL. RESULTS: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL. CONCLUSIONS: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.
