Expression of different isoforms of the B-cell mutator activation-induced cytidine deaminase (AID) in BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients

Abstract

7049 Since the activation-induced cytidine deaminase (AID) enzyme can target non-immunoglobulin (Ig) genes and may even act as a genome-wide mutator, we investigated AID expression in BCR-ABL1-positive ALL and in chronic myeloid leukemia (CML) at the time of progression to blast crisis. On the 61 de novo adult BCR-ABL1-positive ALL patients (pts), AID mRNA and protein were detected in 36 (59%); their expression correlated with BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors at the time of remission. AID expression was also found in lymphoid blast crisis CML (50%), but not in myeloid lineage or in chronic phase CML. Different isoforms of AID were identified: 13/61 (21%) pts expressed the full-length isoform; 19/61 (31%) co-expressed the wild-type and different AID splice variants with deaminase activity (AIDΔE4a, with a 30 bp deletion of exon 4; AIDΔE4, with the exon 4 deletion; AIDins3, with the retention of intron 3–4); 4/61 (7%) expressed the AIDΔE3-E4 isoform without deaminase activity (deletion of exons 2 and 3). To investigate whether AID introduces DNA-single strand breaks, we performed a genome wide analysis by 250K NspI single nucleotide polymorphism (SNP) array. Patients who expressed wild-type AID had a higher number of alterations compared to AID-negative (median copy number alteration of 14 versus 4. respectively, p < 0.03). Recurring copy number abnormalities were identified in genes with an established role in leukemogenesis, such as IKZF1, CDKN2A, CDKN2B, PAX5, MELK, BTG1, and MDS1. Our findings show that BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that can act as mutator outside the Ig gene loci in promoting genetic instability in leukemia cells. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Strategico di Ateneo, GIMEMA Onlus. No significant financial relationships to disclose.