Microenvironment Interactions in Chronic Lymphocytic Leukemia: A Delicate Equilibrium Linking the Quiescent and the Proliferative Pool

The Number of Overlapping AID Hotspots in Germline IGHV Genes Is Inversely Correlated with Mutation Frequency in Chronic Lymphocytic Leukemia

“…Thus, for example, AID can be differentially spliced, leading to different AID isoforms in M-CLL vs U-CLL and thus potential differences in AID activity and function [ 44 ]. It has also been suggested that some as-yet unidentified AID co-factor that is necessary for V region targeting, is not expressed [ 45 ]. Moreover, class switch recombination (CSR), which requires AID targeting to the switch regions (adjacent to the V), has been shown to occur in vivo in many U-CLL cases [ 46 , 47 ], although here it might be argued that CSR and SHM are somewhat independent processes [ 48 ].…”

“…This might also be the case for IGHV4-34, which is intrinsically autoreactive but in CLL is usually mutated [ 32 , 50 , 61 ], perhaps reflecting the need for SHM to reduce self-reactivity. As mentioned above, a critical AID co-factor might not be expressed in U-CLL cells because of the activation/maturation pathway these cells might follow (T-cell dependent vs. T-cell independent [ 32 ]), which would make the AID-expressing subset of lymphocytes unable to generate V region mutations but capable of CSR [ 45 ] and therefore continued interaction with an auto- (or exo-) antigen might drive the proliferative subsets of IgG-positive / AID-positive cells that are often observed in U-CLL [ 26 ].…”