title: Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients.
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; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 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.
authors.affiliation: Department of Institute of Hematology and Medical Oncology, L and A Seràgnoli S Orsola Malpighi Hospital, University of Bologna, Bologna 9-40138, Italy. giovanni.martinelli2@unibo.it
authors.forename: I
authors.initials: I
authors.lastname: Iacobucci
authors.forename: A
authors.initials: A
authors.lastname: Lonetti
authors.forename: F
authors.initials: F
authors.lastname: Messa
authors.forename: A
authors.initials: A
authors.lastname: Ferrari
authors.forename: D
authors.initials: D
authors.lastname: Cilloni
authors.forename: S
authors.initials: S
authors.lastname: Soverini
authors.forename: F
authors.initials: F
authors.lastname: Paoloni
authors.forename: F
authors.initials: F
authors.lastname: Arruga
authors.forename: E
authors.initials: E
authors.lastname: Ottaviani
authors.forename: S
authors.initials: S
authors.lastname: Chiaretti
authors.forename: M
authors.initials: M
authors.lastname: Messina
authors.forename: M
authors.initials: M
authors.lastname: Vignetti
authors.forename: C
authors.initials: C
authors.lastname: Papayannidis
authors.forename: A
authors.initials: A
authors.lastname: Vitale
authors.forename: F
authors.initials: F
authors.lastname: Pane
authors.forename: P P
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: S
authors.initials: S
authors.lastname: Paolini
authors.forename: G
authors.initials: G
authors.lastname: Berton
authors.forename: A
authors.initials: A
authors.lastname: Baruzzi
authors.forename: G
authors.initials: G
authors.lastname: Saglio
authors.forename: M
authors.initials: M
authors.lastname: Baccarani
authors.forename: R
authors.initials: R
authors.lastname: Foà
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D003564:Cytidine Deaminase / Q000235:genetics* / Q000502:physiology; D053904:DNA Breaks, Single-Stranded; D016044:Fusion Proteins, bcr-abl / Q000032:analysis* / Q000235:genetics; D005803:Genes, Immunoglobulin; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; C406060:abl-bcr fusion protein, human; D016044:Fusion Proteins, bcr-abl; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase