Asunto(s)
Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Ligando de CD40/antagonistas & inhibidores , Regulación Leucémica de la Expresión Génica , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Syk/antagonistas & inhibidores , Antígenos CD19/genética , Antígenos CD19/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Ciclohexilaminas/farmacología , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos , Especificidad de Órganos , Oxazinas/farmacología , Cultivo Primario de Células , Piridinas/farmacología , Pirimidinas/farmacología , Transducción de Señal , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Quinasa Syk/genética , Quinasa Syk/inmunología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunologíaRESUMEN
Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-γ was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bet(hi)CD38(hi) cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-γ/IFN-γR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL.