The roles of noncoding RNAs in B-cel lymphomas

Abstract

A large number of aberrantly expressed microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been reported in B-cell lymphomas. However, their role in the pathogenesis of B-cell lymphoma remains largely unknown. In this thesis, the functions of non-coding RNAs were explored in two distinct subtypes of germinal center B-cell (GC-B) derived lymphomas, i.e. classical Hodgkin lymphoma (cHL) and Burkitt lymphoma (BL). In a loss-of-function screen in three cHL cell lines we identified four miRNAs with an effect on cell growth. Follow-up experiments for miR-21-5p showed that this miRNA was upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1. Small RNA sequencing in BL and GC-B cells revealed a clearly aberrant expression profile. In subsequent miRNA loss- and gain-of-function screens we identified 18 miRNAs that affected growth of BL, including some previously reported oncogenic miRNAs. Functional follow-up studies revealed promising target genes for miR-378a-3p and miR-26b-5p. Focusing on MYC-induced lncRNAs revealed 18 candidates that were consistently higher expressed in BL cell lines compared to GC-B cells. Three of these lncRNAs showed effects on BL cell growth in a loss-of-function screen. Further validation experiments of MAFG-AS1 confirmed its effect on growth in BL cell lines. In summary, we identified several aberrantly expressed and MYC-regulated non-coding RNAs, with clear effects on growth of cHL and BL cells, and unveiled their underlying mechanisms in cell growth regulation. Our findings add to the current knowledge about the roles of non-coding RNAs in B-cell lymphomas.