AID expression and IGHV profiling reveal a new subgroup of CLL with early progression and treatment needs

Abstract

Clinical and molecular heterogeneity is a hallmark of chronic lymphocytic leukemia (CLL). Despite considerable progress in developing prognostic tools, accurately predicting disease progression remains elusive for many patients. Activation-induced cytidine deaminase (AID) drives somatic hypermutation and class switch recombination of immunoglobulins and is aberrantly expressed in the peripheral blood (PB) of CLL patients with poor outcomes. While AID's mutagenic activity is linked to lymphoma development, its role in CLL remains controversial. Here, we assess AID expression in CLL patient samples from PB and analyze its association with immunoglobulin heavy chain gene (IGHV) status/usage and time to first treatment (TTFT). Our findings reveal a high-risk CLL subgroup with elevated AID expression and unmutated B-cell receptors rearranging specific IGHV (1-02; 1-69; 3-30, and 4-39). This subgroup represents 36% of unmutated CLLs and 15% of the studied cohort, (n=312), with a significantly shorter TTFT, (mean: 7 months). Furthermore, we suggest that AID expression in this subgroup originates from a constitutively activated microenvironment driven by an antigen restriction. By incorporating AID mRNA expression and IGHV profiling into routine diagnosis, we propose a novel prognostic tool to identify high-risk subgroups. This approach enables early patient stratification, leading to more accurate prognostication and timely treatment decisions.