Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth and survival, possibly through their ability to regulate the expression of specific proliferative and͞or apoptotic genes. However, the HDACi-regulated genes necessary and͞or sufficient for their biological effects remain undefined. We demonstrate that the HDACis suberoylanilide hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping gene set with at least 22% of genes showing altered expression over a 16-h culture period. SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways. Multiple genes within the Myc, type  TGF, cyclin͞cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways were regulated in a manner that favored induction of apoptosis and decreased cellular proliferation. APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death. Overexpression of p16 INK4A and arrest of cells in G1 can suppress HDACi-mediated apoptosis. Although p16 INK4A did not affect the genome-wide transcription changes mediated by SAHA, a small number of apoptotic genes, including BCLXL and B-MYB, were differentially regulated in a manner consistent with attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate that different HDACi alter transcription of a large and common set of genes that control diverse molecular pathways important for cell survival and proliferation. The ability of HDACi to target multiple apoptotic and cell proliferation pathways may provide a competitive advantage over other chemotherapeutic agents because suppression͞loss of a single pathway may not confer resistance to these agents.
Purpose Despite the generally favorable clinical course in follicular lymphoma (FL), a minority of patients have a poor prognosis—with death within 3 years of diagnosis—most often due to transformation to aggressive disease. Patients and Methods In this study, we analyzed the potential of predicting early transformation on the basis of gene expression and immunologic parameters in FL biopsy samples taken at diagnosis. Results At the gene-expression level, FL is a highly uniform disease at the time of diagnosis, precluding the detection of sufficiently validated prognostic gene-expression profiles suitable for a clinical setting. Combinations of differentially expressed genes indicate that immunologic mechanisms play a differential role in the risk of early transformation. Using immunohistochemistry for specific cell populations, the spatial distribution to neoplastic follicles and the activation of CD4–positive T-helper cells (P = .002) and specifically T-helper 1 (P = .004) were shown to be highly discriminatory to predict early transformation. A role for functional modulation of follicular dendritic cells could also be supported (P = .04). Other cell populations, including CD68-positive macrophages and regulatory T cells, were not differentially present. Conclusion These results support the identification of FL as an immunologically functional disease in which an interaction of the tumor cells and the functional composition of the microenvironment determines the clinical behavior.
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