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, Shuki Mizutani

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3622-3627
Number of pages6
JournalBlood
Volume101
Issue number9
DOIs
Publication statusPublished - May 1 2003

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Ataxia Telangiectasia
Phosphorylation
Gene Rearrangement
Missense Mutation
Assays
Leukemia
Genes
Phosphatidylinositol 3-Kinase
Signal transduction
Fibroblasts
Phosphotransferases
Biphenotypic Acute Leukemia
Proteins
Germ-Line Mutation
Signal Transduction
Phenotype
Mutation

ASJC Scopus subject areas

  • Hematology

Cite this

Oguchi, K., Takagi, M., Tsuchida, R., Taya, Y., Ito, E., Isoyama, K., ... Mizutani, S. (2003). Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement. Blood, 101(9), 3622-3627. https://doi.org/10.1182/blood-2002-02-0570

Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement. / Oguchi, Kaoru; Takagi, Masatoshi; Tsuchida, Rika; Taya, Yoichi; Ito, Etsuro; Isoyama, Keiichi; Ishii, Eiichi; Zannini, Laura; Delia, Domenico; Mizutani, Shuki.

In: Blood, Vol. 101, No. 9, 01.05.2003, p. 3622-3627.

Research output: Contribution to journalArticle

Oguchi, K, Takagi, M, Tsuchida, R, Taya, Y, Ito, E, Isoyama, K, Ishii, E, Zannini, L, Delia, D & Mizutani, S 2003, 'Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement', Blood, vol. 101, no. 9, pp. 3622-3627. https://doi.org/10.1182/blood-2002-02-0570
Oguchi, Kaoru ; Takagi, Masatoshi ; Tsuchida, Rika ; Taya, Yoichi ; Ito, Etsuro ; Isoyama, Keiichi ; Ishii, Eiichi ; Zannini, Laura ; Delia, Domenico ; Mizutani, Shuki. / Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement. In: Blood. 2003 ; Vol. 101, No. 9. pp. 3622-3627.
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