Constitutive aid expression in CLL mouse model leads to disease progression, tumor proliferation and diminished survival

MORANDE PABLO; YAN XIAO-YEN; SOTELO NATALIA; PRIETO DANIEL; SEIJA NOÉ; CRISPO MARTINA; CHIORAZZI NICHOLAS; OPPEZZO PABLO

Sydney

Encuentro; Young Investigator´s Meeting 2015 - Presentaciones Orales; 2015

Chronic Lymphocytic Leukemia (CLL) shows a highly variable disease course, partlyexplained by the diverse combinations of somatic mutations whose were recently uncoveredby whole-exome sequencing (WES) analysis. In physiological conditions, the enzymeActivation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) andclass switch recombination (CSR) of the immunoglobulin genes, which are necessary for aneffective immune response. As a trade-off for the benefits brought about by its physiologicalroles, AID can also contribute to cellular transformation and tumor progression by aberrantlymutagenizing genes outside the Ig locus (off-target mutations). We previously described thatprogressive CLL patients aberrantly express AID in CLL B-cells of PB (Oppezzo et al.,Blood 2005), and that its expression is associated with worse patient outcome (Palacios et al.,Blood 2010 and Patten, et al., Blood 2012). The aims of the present work were: a) to evaluatethe role of AID in CLL clonal evolution, and b) to identify AID signature mutations duringdisease progression. To these aims we used the transgenic Eu-TCL1 mice, a murine modelthat mimics a progressive and unmutated CLL disease, and crossed it with a transgenic strainoverexpressing AID under the control of the actin promoter. Double transgenic actin-AID/Eu-TCL1 mice (DT) were viable and showed no evident inborn alterations. Presence at theDNA genomic level of AID and TCL1 genes and gene expression at RNA levels was verifiedby quantitative PCR in PB and spleen cells, for both transgenes. DT mice expressed TCL1and showed higher expression of AID as compared to its TCL1 counterpart, for both PB andspleen cells (n=5, p