APOBEC gene family expression and hallmarks in chronic lymphocytic leukemia

Abstract

Abstract The hallmark activity of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family of cytidine deaminases, including activation-induced deaminase (AID) and APOBEC3 genes, has been detected in somatic mutation signatures by ultra-deep sequencing of the genomes of many cancers, including chronic lymphocytic leukemia (CLL). The acquisition of these mutations is hypothesized to lead to the progression towards aggressive disease in cancer. To examine this in CLL, we tested if increased APOBEC family member gene expression in CLL cells, as measured by microarray and quantitative real time PCR, correlated with worse patient outcome. Higher levels of AID, APOBEC3B, APOBEC3F and APOBEC3H in CLL cells correlated with worse patient outcome, whereas APOBEC3G did not. Interestingly, higher levels of a truncated splice variant of APOBEC3F tended to correlate with better patient outcome. The expression of truncated APOBEC3F may possibly interfere with APOBEC family member mutation activity. To test mutation activity, CLL cells were activated by transfer into NOD-scid IL2Rγnull mice, a xenograft model of human CLL, and hallmark mutation signatures in the expressed immunoglobulin variable region (IGHV) of CLL cells were analyzed by targeted ultra-deep sequencing. Induced IGHV mutation hallmarks consistent with AID were found. These data support the hypothesis that expression and mutation activity of APOBEC family members, such as AID, in CLL cells could lead to adverse patient consequences.