AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL

Simple Summary Cancers, such as chronic lymphocytic leukemia, frequently acquire consecutive somatic mutations in the genome, which contribute to disease progression and treatment resistance. Activation-induced deaminase is an enzyme responsible for generating the highly diverse B cell repertoire but it can also induce substantial collateral damage within the genome of cells. Hence, it is important to assess whether AID contributes to cancer mutations and to the course of disease. This research shows that AID contributes to the acquisition of somatic cancer-specific mutations in a mouse model for chronic lymphocytic leukemia reflected in prolonged overall survival of leukemic mice lacking AID expression. These data should initiate future studies to assess the effect of AID inhibition on the occurrence of drug resistance. Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance.

Automated summary

The study demonstrates that AID contributes to the acquisition of somatic cancer-specific mutations in chronic lymphocytic leukemia, leading to accelerated disease progression and affecting the survival rate of mice. Therefore, further research on the impact of AID inhibition on drug resistance development is crucial.