Estrogen regulation of non-Hodgkin lymphomas and its underlying mechanisms

Most non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), show a higher male to female incidence ratio. The reason for this is not clear, but epidemiological and experimental studies have suggested a role for estrogens in NHL acting via estrogen receptor β (ERβ). My thesis aims to demonstrate the underlying molecular mechanisms of ERβ action in MCL. Secondly, I investigated genes affected in a sex-and female age-dependent manner in DLBCL to identify estrogen-regulated genes. Furthermore, except for the role of endogenous estrogens, the effect of xenoestrogen on NHL was studied. In addition, since the tumor microenvironment (TME) also contributes to tumor cell survival and drug sensitivity, aspects of the lymphoma-TME interaction were investigated. This included stromal cell-mediated ibrutinib (the Bruton tyrosine kinase inhibitor) resistance and how to overcome this resistance in MCL. Paper I. In order to investigate ERβ-mediated effects on MCL tumors, ibrutinib-sensitive and resistant MCL cells were grafted to mice and treated with the ERβ selective agonist diarylpropinitrile (DPN). The transcriptome and chromatin binding of ERβ were studied in Granta-519 MCL tumors in response to the DPN treatment. The results showed that DPN treatment of both ibrutinib sensitive- and resistant MCL tumors in mice resulted in impaired tumor progression. Transcriptome analysis of Granta-519 tumors showed that genes affected by DPN were enriched in several biological processes, including cell-cell adhesion, endothelial mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, individual genes that play a role in MCL progressions, such as SOX11 and MALAT1, were also downregulated. Furthermore, the data indicated an interaction between the lymphoma cells and the tumor microenvironment in response to the ERβ selective agonist. Our results demonstrate how MCL is under the control of ERβ and elucidate the molecular mechanism for the impaired tumor progression. Targeting ERβ with a selective agonist may be an additional choice for treating both ibrutinib sensitive and resistant MCL tumors. Paper II. The aim of this paper was to investigate the sex difference and estrogen effects in DLBCL. For this, we analyzed gene expression data from an RNA sequencing cohort containing 746 DLBCL samples. Our results showed that 1293 genes were differentially expressed between females and males (adj. p-value <0.05). Few genes showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. A gene set enrichment analysis indicated that only 4 out of 13 significant pathways were common between the subtypes (adj. p-value