Fine-tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation

Abstract

We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin and Reed-Sternberg cells of cHL at higher levels than in non-Hodgkin lymphoma subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here, we show that high FOXO3A levels in cHL reflect a B-cell-differentiation-specific pattern. In B cells, FOXO3A expression increases during the process of centroblast to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1α. As factors attenuating FOXO3A expression in cHL, we identified and constitutive activation of extracellular signal-regulated kinase. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL.

Expression of ELF1, a lymphoid ETS domain‐containing transcription factor, is recurrently lost in classical Hodgkin lymphoma

“…The cHL‐associated ELF1 methylation demonstrated in our study does not support the abortive plasma cell hypothesis of HRS cell development (Seitz et al , ; Osswald et al , ). Both analysed normal plasma cell populations, including bone marrow plasma cells and tonsillar plasma cells were unmethylated similar to the other benign B‐cell subpopulations analysed and contrasting them to the cHL cell lines.…”

Revealing the Critical Regulators of Cell Identity in the Mouse Cell Atlas

“…Interestingly, each smaller module is specifically associated with distinct immune cell types ( Figure 3C ). For example, SM3 is associated with neutrophils, and the involved regulons including Stat5a ( Fiévez et al, 2007 ), Foxo3 ( Osswald et al, 2018 ), and Elf1 ( Bjerregaard et al, 2003 ) are associated with neutrophil regulation. SM4 is mainly related to macrophages; correspondingly, many well-known macrophage-related regulators are predicted by our network analysis, such as Irf family genes and Nfkb genes ( Valledor et al, 1998 ).…”

Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation

“…FOXO3 is a transcription factor belonging to the O subclass of the forkhead family. It is thought to be associated with tumorigenesis, immunoregulation, and even longevity of humans [41][42][43][44][45] . Besides, researchers discovered that FOXO3 regulates neurogenesis in adult by interacting with ten-eleven translocation-2 protein 46 and maintains redox balance in neural stem cells coordinating metabolic pathways 47 .…”