Role of AID/APOBEC mutagenesis in evolution of aggressive lymphoid malignancies
In lymphoid malignancies, new mutations acquired by the malignant cancer cell often correlate with aggressive disease and worse patient outcome. The mechanism for generating new mutations in these cancers is not clear. Research by our lab and others has suggested that abnormal activity of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family of cytidine deaminases may be involved. In particular, activation-induced deaminase (AID) and APOBEC3 family members have been implicated in mutational signatures detected in cancer genomes. If mutations caused by these APOBEC family members are involved in the evolution towards aggressive disease, then higher expression of these genes should correlate with worse patient outcome. Indeed, in our study of chronic lymphocytic leukemia (CLL) patient samples, we found higher expression of AID and some APOBEC3 family members correlated with faster time to first treatment and shorter overall patient survival.
In collaboration with the laboratories of W. Richard Burack, M.D., Ph.D., in the in the department of Pathology and Laboratory Medicine, Clive S. Zent, M.D. in the Wilmot Cancer Institute, Tom MacCarthy, Ph.D. at Stony Brook University, Nicholas Chiorazzi, M.D., and Kanti Rai, M.D. at the Feinstein Institute for Medical Research, we have been studying the mutational activity in CLL and plan to extend these studies to other lymphoid malignancies.
Kaplan-Meier curves of CLL patients with AID+ (red) or AID- (blue) expressing cells showing that that AID+ patients have a significantly shorter Time to First Treatment (left graph, AID+: n = 58, Median TFT = 52 months, AID-: n = 55, Median TFT = 124 months; P = 0.0015) and shorter Overall Survival (right graph, AID+: n = 57, Median survival = 132 months, AID-: n = 55, Median survival = 228 months; P < 0.0001).
Our long-term goal is to understand the mutagenesis mechanisms occurring in lymphoid malignancies underlying the evolution of aggressive disease. This understanding will aid in developing strategies to prevent the evolution of lymphoid malignancies towards aggressive disease and therefore increase patient survival.