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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-02-0570.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3622-3627
NEOPLASIA
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
From the Department of Pediatrics and Developmental
Biology, Postgraduate Medical School, Tokyo Medical and Dental
University, Tokyo, Japan; Radiobiology Division, National
Cancer Center Research Institute, Tokyo, Japan; Department
of Pediatrics, Hirosaki University School of Medicine, Aomori,
Japan; Department of Pediatrics, Showa University
Fujigaoka Hospital, Yokohama, Kanagawa, Japan; Department
of Pediatrics, Saga Medical School, Nabeshima, Saga,
Japan; and Department of Experimental Oncology, Istituto
Nazionale Tumori, Milano, Italy.
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 7 patients studied, 1 showed a germline missense ATM mutation
(8921C>T; Pro2974Leu), located in the
phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays,
the ATM mutant 8921T could only partially rescue the radiosensitive
phenotype of AT fibroblasts, and in an 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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