title: Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.
abstract: 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.
authors.affiliation: Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Oguchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Rika
authors.initials: R
authors.lastname: Tsuchida
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.forename: Keiichi
authors.initials: K
authors.lastname: Isoyama
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.forename: Laura
authors.initials: L
authors.lastname: Zannini
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
mesh_terms: D001260:Ataxia Telangiectasia / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001859:Bone Neoplasms / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005816:Genetic Complementation Test; D018095:Germ-Line Mutation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007948:Leukemia, Monocytic, Acute / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D051788:Myeloid-Lymphoid Leukemia Protein; D012516:Osteosarcoma / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497422:KMT2A protein, human; C576324:ATM protein, human