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 language | English |
|---|---|
| Pages (from-to) | 3622-3627 |
| Number of pages | 6 |
| Journal | Blood |
| Volume | 101 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - May 1 2003 |
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ASJC Scopus subject areas
- Hematology
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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 journal › Article
}
TY - JOUR
T1 - Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement
AU - Oguchi, Kaoru
AU - Takagi, Masatoshi
AU - Tsuchida, Rika
AU - Taya, Yoichi
AU - Ito, Etsuro
AU - Isoyama, Keiichi
AU - Ishii, Eiichi
AU - Zannini, Laura
AU - Delia, Domenico
AU - Mizutani, Shuki
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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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U2 - 10.1182/blood-2002-02-0570
DO - 10.1182/blood-2002-02-0570
M3 - Article
VL - 101
SP - 3622
EP - 3627
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -