AID induces intraclonal diversity and genomic damage in CD86⁺ chronic lymphocytic leukemia cells

Abstract

The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL.

AID/APOBEC deaminases and cancer

“…Concomitantly, by comparing mutation frequencies in AID pro- versus deficient mice, it soon became clear that AID not only initiates the hypermutation of Ig genes but to a lesser extent also of many non-Ig genes, which are not properly protected by high-fidelity DNA repair, demonstrating off-target DNA damage induced by AID [109]. In addition, several reports show that many B cell lymphomas harbor subclonal heterogeneity at the Ig locus, which indicates ongoing AID activity during disease progression [110-113]. Hence, AID may not only contribute to malignant transformation but also to clonal evolution of B cell malignancies.…”

HSP90 inhibitors decrease AID levels and activity in mice and in human cells

“…Continued AID expression in lymphoma and leukemia can contribute to disease progression and hence be a relevant target of HSP90 inhibitors . Indeed, AID expression correlates with poor outcome in CLL , B‐ALL , and CML . Here, we show that 17‐DMAG increases survival in a B‐ALL mouse model in which AID clearly confers increased aggressiveness.…”

“…AID is also expressed in non GC‐derived hematological malignancies such as chronic myelogenous leukemia (CML) , B‐cell acute lymphoblastic leukemia (B‐ALL) and, chronic lymphocytic leukemia (CLL) . In these leukemia, AID favors disease progression and correlates with poorer outcome . Hence, also in this context, AID inhibition could have therapeutic value .…”

AIDing cancer treatment: Reducing AID activity via HSP90 inhibition

“…Indeed, there is convincing evidence that AID‐dependent mutations also accumulate outside the antibody locus and that AID is responsible for a panel of chromosomal translocations as a by‐product of aberrant CSR . Hence, AID off‐target damage has been shown to be involved in lymphomagenesis and clonal evolution of B‐cell malignancies . Finally, AID was shown to be also expressed in non‐B‐cell tissue, particularly in many solid cancers, whereupon AID was also suggested to be a tumorigenic factor in stomach, breast, lung, liver, and colon cancers .…”

“…In this regard, AID may support clonal evolution by initiating subclonal mutations, which would eventually confer a growth advantage to the cell (Fig. ) . Especially during therapy, tumors have to quickly adapt to a drug to overcome its anti‐cancer activity.…”