leukemia patient with MLL gene rearrangement Missense mutation and defective function of ATM in a childhood acute

AbstractThe possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL+) was investigated. Of the seven patients studied, one showed a germline missense ATM mutation (8921C T; Pro to Leu at codon 2974), located in the PI-3 kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Furthermore, the introduction of 8921T in U2OS cells, characterized by a normal ATM/p53 signal transduction, caused a significant reduction of in vivo p53-Ser15 phosphorylation, suggesting a dominant negative effect of the mutant ATM over the wild-type protein.Our finding in this patient suggests that altered function of ATM plays some pathogenic roles in the development of MLL+ leukemia. IntroductionAtaxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency. The responsible gene, ATM (ataxia telangiectasia mutated), is located on chromosome 11q22-23 and encodes a 350 kDa nuclear protein with a carboxy terminal domain From bloodjournal.hematologylibrary.org by guest on June 2, 2013. For personal use only.