Targeting GLI3 in Diffuse Large B-cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is further subdivided into activated B cell (ABC) and germinal center B cell (GCB) like subtypes. Each subtype responds to therapy in different ways and the association of many signaling pathways is important in understanding tumor formation and ultimately helping in the prevention of cancer development. GLI proteins, which are members of the hedgehog (HH) signaling pathway, are important transcription factors because they regulate target gene expression by directly binding to specific sequences (binding sites) in the corresponding promoter regions. We investigated GLI1-3 expression by qPCR in 12 DLBCL cell lines belonging to ABC and GCB subtypes. An increase in GLI3 expression in the GCB subtype was observed, but that did not reach statistical significance, possibly due to the small sample size. Therefore, publicly available data published on Gene Expression Omnibus (GSE10846) was used to analyze the expression of GLI1, GLI2 and GLI3 in the DLBCL subtypes. We found an increase in GLI2 and GLI3 expression in GCB DLBCL compared with ABC DLBCL. The role of GLI1 and 2 have been studied in DLBCL, however, no studies have investigated the role of GLI3. We therefore targeted GLI3 in GCB DLBCL using RNA interference and found a decrease in cell proliferation corresponding to a reduction in GLI3 mRNA expression. Taken together, these studies show that GLI3 mRNA is elevated in GCB DLBCL patients and its knockdown reduces cell growth.