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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-02-0570.
Submitted February 21, 2002
Accepted December 10, 2002
Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement
Kaoru Oguchi, Masatoshi Takagi, Rika Tsuchida, Yoichi Taya, Etsuro Ito, Keiichi Isoyama, Eiichi Ishii, Laura Zannini, Domenico Delia, and Shuki Mizutani*
Department of Pediatrics and Developmental Biology, Postgraduate Medical School,Tokyo Medical acd Dental UniversityBiology, Tokyo, Japan
Department of Experimental Oncology, Instituto Nazionale Tumori, Milan, Italy
Radiobiology Division, National Cancer Center Research Institute, Tokyo, Japan
Department of Pediatrics, Hirosaki University school of medicine, Hirosaki, Japan
Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan
Department of Pediatrics, Saga Medical School, Nabeshima, Japan
* Corresponding author; email: smizutani.ped{at}tmd.ac.jp.
The 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.
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