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27.10.2018 | Original Article

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

verfasst von: Kristina Zaprazna, Kamila Reblova, Veronika Svobodova, Lenka Radova, Vojtech Bystry, Jiri Baloun, Kristina Durechova, Nikola Tom, Tomas Loja, Martina Buresova, Kamila Stranska, Alexandra Oltova, Michael Doubek, Michael L. Atchison, Martin Trbusek, Jitka Malcikova, Sarka Pospisilova

Erschienen in: Annals of Hematology | Ausgabe 2/2019

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Abstract

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.

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Titel: Activation-induced deaminase and its splice variants associate with trisomy 12 in chronic lymphocytic leukemia
verfasst von: Kristina Zaprazna
Kamila Reblova
Veronika Svobodova
Lenka Radova
Vojtech Bystry
Jiri Baloun
Kristina Durechova
Nikola Tom
Tomas Loja
Martina Buresova
Kamila Stranska
Alexandra Oltova
Michael Doubek
Michael L. Atchison
Martin Trbusek
Jitka Malcikova
Sarka Pospisilova
Publikationsdatum: 27.10.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology / Ausgabe 2/2019
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-018-3520-5

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