Activation-induced deaminase and its splice variants associate with trisomy 12 in chronic lymphocytic leukemia

• Published in: Annals of hematology 2019-02, Vol.98 (2), p.423-435
• Main Authors: Zaprazna, Kristina, Reblova, Kamila, Svobodova, Veronika, Radova, Lenka, Bystry, Vojtech, Baloun, Jiri, Durechova, Kristina, Tom, Nikola, Loja, Tomas, Buresova, Martina, Stranska, Kamila, Oltova, Alexandra, Doubek, Michael, Atchison, Michael L., Trbusek, Martin, Malcikova, Jitka, Pospisilova, Sarka
• Format: Article
• Language: English
• Subjects: Aged; Alternative Splicing; Animals; Chromosomes, Human, Pair 12 - enzymology; Chromosomes, Human, Pair 12 - genetics; Computer Simulation; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - chemistry; Cytidine Deaminase - genetics; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Hematology; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Middle Aged; Models, Biological; Molecular Dynamics Simulation; Mutation; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Oncology; Original Article; Trisomy - genetics; Trisomy - pathology
• ISSN: 0939-5555; 1432-0584
• DOI: 10.1007/s00277-018-3520-5

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.