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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia / pathology
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Ataxia Telangiectasia Mutated Proteins
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Bone Neoplasms / pathology
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Cell Cycle Proteins
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Cell Line / radiation effects
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Cell Transformation, Neoplastic / genetics
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Chromosomes, Human, Pair 11 / genetics
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DNA Mutational Analysis
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DNA, Neoplasm / genetics
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DNA-Binding Proteins / genetics*
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Female
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Genes, Dominant
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Genetic Complementation Test
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Germ-Line Mutation
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Histone-Lysine N-Methyltransferase
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Humans
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Infant
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Leukemia, Monocytic, Acute / genetics
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Male
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Mutation, Missense*
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Myeloid-Lymphoid Leukemia Protein
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Osteosarcoma / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / genetics*
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Protein Structure, Tertiary
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Proto-Oncogenes*
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Radiation Tolerance / genetics
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Signal Transduction
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Transcription Factors*
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Translocation, Genetic
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
Substances
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Cell Cycle Proteins
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DNA, Neoplasm
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DNA-Binding Proteins
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KMT2A protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases