Vitamin D receptor expression in germinal centre type diffuse large B-cell lymphoma cells is associated with vitamin D insensitivity

Objective: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphomas (NHLs) often sub-classified into major germinal centre (GC) and activated B-cell (ABC) cell-of-origin types. We have previously shown vitamin D receptor (VDR) expression in plasmablastic ABC-DLBCL cells and demonstrated inhibition of their growth by exogenous vitamin D (VitD3); however, the vitamin D biology of GC-DLBCL cells remained unclear. Design/methods: Study of VDR and related molecule expression and vitamin D response across a panel of DLBCL and myeloma cell lines by western blot, qPCR, flow cytometry and cell counting techniques. Analysis of gene expression and ChIP-seq in published cell line and/or primary DLBCL datasets. Results: We show that some BCL6hi GC-DLBCL cell lines express low levels of VDR, but appear resistant to VitD3, and associate VDR positivity in both GC- and ABC-DLBCL cell lines with the poor prognosis plasmacytic/activation marker CD38. ChIP-seq data suggest that VDR may be a direct BCL6 target. Functionally, VitD3 and the EB-1089 analogue can reduce growth, inhibit MYC expression and increase CD38 expression by 50-400% on ABC-DLBCL and myeloma but not GC-DLBCL cells. CD38 is also activated by VitD3 treatment of human peripheral B cell lines, where VDR can bind to the CD38 locus, suggesting direct regulation. Conclusions: Combined VDR and cell-of-origin assessment may contribute to a greater understanding of vitamin D's role in mature B-cell lymphoma and its interplay with BCL6 and MYC.