Clonal evolution of pre-malignant B-cells in the absence of AID
Speaker: Guillermo Rodríguez-Hernández
Centro de Investigación del Cáncer, CIC-IBMCC, lab.13
Salón de Actos del Centro de Investigación del Cáncer
Infections during early childhood have been associated to the development of childhood B-cell acute leukemia (B-ALL). We recently showed that natural exposure to infectious pathogen induced development of overt B-ALL in mouse models mimicking the human genetic predisposition to B-ALL. In addition to its role as central effector of somatic hypermutation and class-switch recombination in B-cells, AID contributes to B-cell transformation. Likewise, a recent mouse model of endemic Burkitt’s lymphoma, which is caused by chronic infection, identified AID as driver of B-cell lymphomagenesis. Ex vivo experimental studies have suggested that the expression of AID in precursor B cells may promote clonal evolution towards leukemia. Conversely, recent studies have revealed that clonal evolution of premalignant B-cell precursors toward leukemia as a result of in vivo infection exposure takes place through acquisition of secondary genetic events no related to mutated hotspots for AID activity in both patient-derived B-ALL and mouse models mimicking the human genetic predisposition to B-ALL. Based on these observations we examined here, in two genetic approaches, whether AID is required for clonal evolution of pre-malignant B-cells in the etiology of infection-associated B-ALL. Surprisingly, however, latency, penetrance and genetic characteristics of B-ALL was not affected by genetic deletion of Aid in Pax5-haploinsufficient mice, suggesting that AID was dispensable for clonal evolution in this model. In a gain of function experiment, we next showed that the generation of AID off-target mutagenic activity by premature AID expression in precursor B-cells does not promote B-ALL development. Likewise, AID targets are not enriched within the drivers identified in human B-ALL. Overall these results suggest that natural infectious stimuli promote malignant B-cell transformation through AID-independent mechanisms and may have implications for the clinical use of PI3Kδ or Bruton’s tyrosine kinase inhibitors in B-cell leukemias.