Mutation analysis of the Nijmegen Breakage Syndrome gene (NBS1) in nineteen patients with acute myeloid leukemia with complex karyotypes

The chromosomal instability disorder Nijmegen Breakage Syndrome (NBS) is caused by germ line mutations in the NBS1 gene. It is associated with immune deficiency, cellular hypersensitivity to ionizing radiation, and high susceptibility to lymphoid malignancies due to a defect in DNA double strand break repair. Since genetic instability has been discussed as a cause in acute myeloid leukemia (AML) with complex chromosomal aberrations, mutations in the NBS1 gene might be found in this AML subgroup. In this study, we analyzed 19 patients with AML and complex chromosomal aberrations for mutations in the NBS1 gene. Tumor DNA was analyzed by dHPLC analysis and all amplicons showing shifts were directly sequenced. One sample was found to be heterozygous for a novel 5 bp deletion in intron 12 (IVS12-53del5). By RT-PCR analysis the expected transcript and an additional faint product with skipped exon 13 was observed, indicative of aberrant splicing. This exon codes for part of the binding site of the NBS1 gene product, nibrin, to MRE11. However, we also found that all controls showed this phenomenon. Thus, the IVS12-53del5 is not responsible for the skipping of exon 13 and most probably represents a rare polymorphism. We found no further NBS1 mutations among the AML samples. Although the number of the analyzed samples is small, our study indicates that NBS1 mutations are not common in AML with a complex karyotype.