Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement.
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.
Oguchi
Kaoru
K
Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University, Tokyo, Japan.
Takagi
Masatoshi
M
Tsuchida
Rika
R
Taya
Yoichi
Y
Ito
Etsuro
E
Isoyama
Keiichi
K
Ishii
Eiichi
E
Zannini
Laura
L
Delia
Domenico
D
Mizutani
Shuki
S
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
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