AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

The enzyme activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes, critical actions for an effective adaptive immune response. However, in addition to the benefits generated by its physiological roles, AID is an etiological factor for the development of human and murine leukemias and lymphomas. This review highlights the pathological role of AID and the consequences of its actions on the development, progression, and therapeutic refractoriness of chronic lymphocytic leukemia (CLL) as a model disease for mature lymphoid malignancies. First, we summarize pertinent aspects of the expression and function of AID in normal B lymphocytes. Then, we assess putative causes for AID expression in leukemic cells emphasizing the role of an activated microenvironment. Thirdly, we discuss the role of AID in lymphomagenesis, in light of recent data obtained by NGS analyses on the genomic landscape of leukemia and lymphomas, concentrating on the frequency of AID signatures in these cancers and correlating previously described tumor-gene drivers with the presence of AID off-target mutations. Finally, we discuss how these changes could affect tumor suppressor and proto-oncogene targets and how they could be associated with disease progression. Collectively, we hope that these sections will help to better understand the complex paradox between the physiological role of AID in adaptive immunity and its potential causative activity in B-cell malignancies.

Automated summary

This review article discusses the dual role of the enzyme activation-induced cytidine deaminase (AID) in adaptive immunity and B-cell malignancies, emphasizing its pathological effects as a causative factor in leukemia and lymphomas. It summarizes the expression and function of AID in normal B lymphocytes, evaluates potential causes for AID expression in leukemic cells, and discusses its role in lymphomagenesis based on recent genomic landscape analyses of leukemia and lymphomas. The review also touches upon the correlation between AID off-target mutations and tumor-gene drivers in these cancers, and how these mutations could impact disease progression.