The only reported regulatory effects of NHL-associated translocations so far are those affecting single genes close to the breakpoint. However, we show that these translocations can upregulate a large set of genes affected entire chromosome arms. Our finding has large implications for understanding the global functioning of the nucleus, both in the context of healthy cells as well as in the context of lymphoma formation. Especially because overexpressed genes in MCL patients are enriched in the exact same chromosomal regions as those genes affected when we generate translocations in the laboratory. Overall, our results thus allow us thus to provide a clear set of genes to be explored further for their tumorigenic effects, their use to build better murine MCL models, as well as their therapeutic potential in the context of NHL.
A second important result is that we show that the activation and organization of the DNA prior to translocation formation influence the effect of translocations on gene expression. In other words, pre-existing genomic characteristics determine the potential of translocations to generate effects that can induce tumor formation. This finding is especially important now that single-cell approaches enable the identification of more and more cell subtypes. Based on our findings, we will be able to predict translocation-induced effect in these cell subtypes, allowing to better pinpoint the cell type of origin of NHLs.
While our study focuses on understanding the very early effects of lymphoma formation, we believe that our findings have a far more general implication as explained next. Overall, we show that the effects of translocations are far broader than initally thought. As many tumors harbour translocations or other large genomic aberrations, known as structural variants, that usually occur very early during disease development, our results can have a wide impact for the understanding of tumor formation.
