Abstract
The main reason for the unfavorable clinical outcome of BCR–ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR–ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR–ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDΔE4a, with a 30-bp deletion of exon 4; AIDΔE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDΔE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-ΔE4a and AID-ΔE3E4 variants, whereas the C-terminal-truncated AID-ΔE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR–ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.
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Acknowledgements
This work was supported by AIL, European LeukaemiaNet, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, Ateneo 60% grants and Gimema Onlus Working Party ALL and CML. We specially thank Serena Formica (University of Bologna) and Annalisa Astolfi (University of Bologna) for help in performing SNP arrays, and Barbara Lama (University of Bologna) for collecting clinical data. We also acknowledge all the people who took care of the patients involved in the GIMEMA studies (see Appendix in Supplementary Information). Conception and design II, MB, GM; Provision of study materials or patients, CP, AV, FP; PPP; SP, GP, RF; Collection and assembly of data, AL; AF; SS; FA; SC; MM; FP, MV; Data analysis and interpretation II, DC, FM, AB, EO; Paper writing II; final approval of paper, GM.
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Iacobucci, I., Lonetti, A., Messa, F. et al. Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR–ABL1-positive acute lymphoblastic leukemia patients. Leukemia 24, 66–73 (2010). https://doi.org/10.1038/leu.2009.197
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DOI: https://doi.org/10.1038/leu.2009.197
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