Open AccessActivation-induced deaminase and its splice variants associate with trisomy 12 in chronic lymphocytic leukemia
Author(s) -
Kristína Zápražná,
Kamila Réblová,
Veronika Svobodová,
Lenka Radová,
Vojtěch Bystrý,
Jiří Baloun,
Kristina Ďurechová,
Nikola Tom,
Tomáš Loja,
Martina Burešová,
Kamila Stránská,
Alexandra Oltová,
Michael Doubek,
Michael L. Atchison,
Martin Trbušek,
Jitka Malčíková,
Šárka Pospı́šilová
Publication year - 2018
Publication title -
annals of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.079
H-Index - 80
eISSN - 1432-0584
pISSN - 0939-5555
DOI - 10.1007/s00277-018-3520-5
Subject(s) - somatic hypermutation , cytidine deaminase , activation induced (cytidine) deaminase , ighv@ , biology , chronic lymphocytic leukemia , immunoglobulin class switching , genetics , trisomy , mutation , cancer research , gene , microbiology and biotechnology , leukemia , antibody , b cell
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.