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Molecular mechanisms of mature B cell lymphomagenesis

Final Report Summary - BCLYM (Molecular mechanisms of mature B cell lymphomagenesis)

Lymphomas arise from the neoplastic transformation of either T or B lymphocytes. Strikingly, about 95% of all lymphomas originate from B, rather than T lymphocytes, and most of them (75-85%) are thought to be counterparts of mature B cells that have been germinal center (GC)-experienced. Mature B/germinal center neoplasias include diffuse large B cell lymphoma, follicular lymphoma, Burkitt lymphoma or B cell chronic lymphocytic leukemia. It is estimated that about 60000-80000 new cases of mature B cell lymphomas are diagnosed every year in Europe alone (http://www.euro.who.int/en/home). GC B cells are unique in that they remodel their immunoglobulin genes to generate antibodies that are more fit to fight infection. This remodelling is initiated by an enzyme called AID, and could be at the core of B cell propensity to undergo malignant transformation. The BCLYM proposal aimed at understanding the molecular mechanisms of B cell lymphomagenesis from two different perspectives: by studying the regulation of AID and by assessing the contribution of microRNAs –small RNA molecules that regulate the expression of genes- to the function of mature B cells.

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.