Final Report Summary - BCLYM (Molecular mechanisms of mature B cell lymphomagenesis)
Others and we had previously found that AID function is not limited to immunoglobulin genes; instead, it can promote mutations and chromosomal translocations -illegitimate junctions between two chromosomes- frequently found in lymphomas. With BCLYM we have uncovered several ways in which AID is regulated so that its beneficial activity during the immune response is preserved, while its hazardous activity on the genome is minimal. On one hand, the amount of AID present in the cell is very tightly controlled within functional range (Sernandez 2008) and this is partly achieved through a microRNA called miR-181b that keeps AID levels in check (de Yebenes 2008). In addition, the initial lesions introduced by AID can be corrected afterwards through a repair pathway that is sequence-dependent (Pérez-Durán 2012). Our current efforts are focused on understanding the features that make a gene visible to AID lesions while others are untouched by this activity. In addition, we have engineered mice where AID expression can be switched on in a given tissue, which will teach us on the oncogenic potential of AID in vivo.
AID acts in the context of GCs, where B cells are in a delicate balance between cell proliferation and death. We have found that microRNAs are critical regulators of these events. On one hand, we have shown that mice whose B cells have been depleted of microRNAs accumulate autoreactive antibodies and develop autoimmune disease (Belver 2010). On the other we have identified miR-181b as a direct regulator of AID (de Yebenes 2008), miR-217 as a positive regulator of the GC that acts as an oncogene (de Yebenes 2014) and miR-28 as a negative regulator of the GC that acts as a tumor suppressor. Therefore, an intertwined network of microRNAs link the correct function of GC B cells with their lymphomagenic transformation. microRNA-based therapies hold great promise for clinical intervention. Based on our results, we are currently exploring avenues for lymphoma therapy using microRNAs.