FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.

[hodgkin lymphoma, classical]

Recently we have shown that the transcription factor FOXO 1 , highly expressed in B cells , is downregulated in classical Hodgkin lymphoma (cHL ). As primary mediastinal B cell lymphoma (PMBL ) has similarities with the cHL transcription program we investigated FOXO 1 expression in this entity . By using immunohistochemistry we found that FOXO 1 was absent or expressed at low levels in 19 of 20 primary PMBL cases . PMBL cell lines reproduce the low FOXO 1 expression observed in primary cases . By analyzing gene expression profiling data we found that FOXO 1 expression inversely correlated with JAK 2 in PMBL cases . Targeting JAK 2 activity by the small molecular weight inhibitor TG 101348 resulted in upregulation of FOXO 1 mRNA and protein expression in MedB-1 and U 2940 cell lines , and the MYC inhibitor 10058 -F 4 increased FOXO 1 mRNA in MedB-1 cells . Moreover , in MedB-1 cells FOXO 1 expression was strongly upregulated by the inhibitor of DNA methylation 5 -aza-2 -deoxycytidine and by the histone deacetylase inhibitor trichostatin A . Since FOXO 1 promoter was unmethylated , this effect is most likely indirect . FOXO 1 activation in the FOXO 1 -negative Med-B 1 cell line led to growth arrest and apoptosis , which was accompanied by repression of MYC and BCL 2 L 1 /BCLxL . Thus , FOXO 1 repression might contribute to the oncogenic program and phenotype of PMBL .