Activation-induced cytidine deaminase (AID) is a mutator enzyme essential for somatic hypermutation (SHM) and class switch recombination (CSR) during effective adaptive immune responses. Its aberrant expression and activity have been detected in lymphomas, leukemias, and solid tumors. In chronic lymphocytic leukemia (CLL) increased expression of alternatively spliced AID variants has been documented. We used real-time RT-PCR to quantify the expression of AID and its alternatively spliced transcripts (AIDΔE4a, AIDΔE4, AIDivs3, and AIDΔE3E4) in 149 CLL patients and correlated this expression to prognostic markers including recurrent chromosomal aberrations, the presence of complex karyotype, mutation status of the immunoglobulin heavy chain variable gene, and recurrent mutations. We report a previously unappreciated association between higher AID transcript levels and trisomy of chromosome 12. Functional analysis of AID splice variants revealed loss of their activity with respect to SHM, CSR, and induction of double-strand DNA breaks. In silico modeling provided insight into the molecular interactions and structural dynamics of wild-type AID and a shortened AID variant closely resembling AIDΔE4, confirming its loss-of-function phenotype.

Central European Institute of Technology Center of Molecular Medicine Masaryk University Kamenice 5 A35 625 00 Brno Czech Republic

Central European Institute of Technology Center of Molecular Medicine Masaryk University Kamenice 5 A35 625 00 Brno Czech Republic Department of Internal Medicine Hematology and Oncology Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

Department of Biomedical Sciences School of Veterinary Medicine University of Pennsylvania Philadelphia PA USA

Department of Internal Medicine Hematology and Oncology Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

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