BioProject

Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. More...

Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Also 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 muta-tional 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. Less...