IntroductionFOXO1 belongs to the subgroup O of forkhead transcription factors (FOX), which share the highly conserved forkhead DNAbinding domain. This O subgroup consists of the 4 members, FOXO1, FOXO3, FOXO4, and FOXO6. 1 FOXO transcription factors control different cellular processes, such as stress response, proliferation, apoptosis, and cell differentiation. 2 FOXO target genes include the cell-cycle regulators CDKN1A and CDKN1B, proapoptotic genes BIM, PMAIP1/NOXA, and FASL as well as oxidative stress protectors SOD2 and CAT. 1,3,4 FOXO1 is of particular interest in B cells because it is highly expressed (http://biogps.gnf.org) and plays a nonredundant role in B-cell differentiation by activating recombination activating genes Rag1 and Rag2 and germinal center (GC) genes Bcl6 and Aicda. [5][6][7] In addition, FOXO1 was reported to be a regulator of B-cell death, and its inactivation by B-cell receptor signaling to AKT/PKB kinase was found to be critical for survival of mature B cells. 8 Several other kinases, including the IB kinase 9 and ERK, 10 have been identified to phosphorylate and facilitate nuclear export of FOXO proteins.It is well documented that the oncogenic program of B-cell lymphomas (BCLs) is tightly related to the survival program of their nontransformed precursor cells. In the majority of nonHodgkin BCLs, the oncogenic program is established as an error of normal GC processes (ie, somatic hypermutation and class switch recombination), which facilitate mutations of tumor suppressor genes and translocation of oncogenes. 11 Execution of the oncogenic program in these lymphomas requires the maintenance of the GC program and the prevention of post-GC differentiation steps (eg, by BCL6 and PAX5 translocation) 12 and probably by deregulation of other transcription factors regulating GC phenotype and terminal differentiation of B cells. 13 Unlike other types of BCLs, neoplastic cells of classical Hodgkin lymphoma (cHL) lose most of their B-cell phenotype. 14 At the same time, Hodgkin and Reed-Sternberg (HRS) cells express many genes of activated B cells, indicating that the oncogenic program of cHL may arise in the process of deregulation of mechanisms, controlling activity of NF-B, 15 ERK, 16 and JAK/STAT 17 pathways in activated B cells. In addition, AKT and ERK kinases are frequently constitutively activated in different B-lymphoma entities, including follicular lymphoma (FL), 18 diffuse large BCL (DLBCL), 19 Burkitt lymphoma (BL), 20 and cHL. 21,22 Therefore, it has been hypothesized that FOXO1 inactivation might be a common event contributing to lymphomagenesis in several lymphoma entities. 8 Given the proposed critical role of inactivation of FOXO1 function in BCLs, we investigated FOXO1 expression in different BCL entities. Unexpectedly, whereas FOXO1 expression was maintained in majority of non-Hodgkin lymphomas (NHLs), downregulation was observed in cHL and lymphocyte-predominant Hodgkin lymphoma (LPHL). We found that re-expression of FOXO1 inhibited proliferation and induced apoptosis in ...

The transcription factor KLF4 may act both as an oncogene and a tumor suppressor in a tissue-depending manner. In T-and pre-B-cell lymphoma, KLF4 was found to act as tumor suppressor. We found the KLF4 promoter methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas, namely, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, and in classic Hodgkin lymphoma (cHL) cases. Promoter hypermethylation was associated with silencing of KLF4 expression. Conditional overexpression of KLF4 in Burkitt lymphoma cell lines moderately retarded proliferation, via cell-cycle arrest in G 0 / G 1 . In the cHL cell lines, KLF4 induced massive cell death that could partially be inhibited with Z-VAD.fmk. A quantitative reverse-transcribed polymerase chain reaction array revealed KLF4 target genes, including the proapoptotic gene BAK1. Using an shRNA-mediated knock-down approach, we found that BAK1 is largely responsible for KLF4-induced apoptosis. In addition, we found that KLF4 negatively regulates CXCL10, CD86, and MSC/ ABF-1 genes. These genes are specifically up-regulated in HRS cells of cHL and known to be involved in establishing the cHL phenotype. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may favor lymphoma survival by loosening cellcycle control and protecting from apoptosis. (Blood. 2010;116(9):1469-1478)

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