Although much progress has been made in recent years in understanding the molecular pathogenesis of CLL, new therapeutic approaches are critical to improving patient outcome. One attractive approach is differentiation therapy, in which the malignant B cells are induced to mature into non-replicative cells with a shorter lifespan. We have shown previously that the natural product Bryostatin 1 induces differentiation of CLL cells through activation of the transcription factor STAT1. To identify genes activated by STAT1 that mediate Bryostatin 1-induced differentiation of CLL cells we used gene expression microarrays. Using this approach, we identified seven genes that were potential STAT1 target genes, including GADD45β, IFI16, caspase 3, topoisomerase I, and the known STAT1 target IRF-1. Given the limitations of genetically manipulating primary CLL cells, we evaluated whether B lymphocytic cell lines recapitulated the molecular and cellular differentiation responses to Bryostatin 1 that we observed in CLL cells. We found that Bryostatin 1 is a potent inducer of differentiation of CESS B lymphoblastoid cells, as measured by growth arrest, downregulation of MHC II, and IgG secretion. Bryostatin 1 also induced signaling events in CESS cells similar to those observed in CLL cells, including activation of STAT1 and induction of STAT1 target genes. These findings suggest that STAT1 and its targets may be important mediators of malignant B cell differentiation and that the CESS cell line can be used to further study the potential clinical application of differentiation therapy in CLL.

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