Reference - Detail
| RRC ID | 39950 |
|---|---|
| Author | Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T. |
| Title | Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. |
| Journal | Blood |
| Abstract |
Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human malignancy. An internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3/ITD) is found in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leukocytosis and a poor prognosis. On the other hand, mutations of the c-KIT gene, which have been found in mast cell leukemia and AML, are clustered in 2 distinct regions, the JM domain and D816 within the activation loop. This study was designed to analyze the mutation of D835 of FLT3, which corresponds to D816 of c-KIT, in a large series of human hematologic malignancies. Several kinds of missense mutations were found in 30 of the 429 (7.0%) AML cases, 1 of the 29 (3.4%) myelodysplastic syndrome (MDS) cases, and 1 of the 36 (2.8%) acute lymphocytic leukemia patients. The D835Y mutation was most frequently found (22 of the 32 D835 mutations), followed by the D835V (5), and D835H (1), D835E (1), and D835N (1) mutations. Of note is that D835 mutations occurred independently of FLT3/ITD. An analysis in the 201 patients newly diagnosed with AML (excluding M3) revealed that, in contrast to the FLT3/ITD mutation (n = 46), D835 mutations (n = 8) were not significantly related to the leukocytosis, but tended to worsen disease-free survival. All D835-mutant FLT3 were constitutively tyrosine-phosphorylated and transformed 32D cells, suggesting these mutations were constitutively active. These results demonstrate that the FLT3 gene is the target most frequently mutated to become constitutively active in AML. |
| Volume | 97(8) |
| Pages | 2434-9 |
| Published | 2001-4-15 |
| DOI | 10.1182/blood.v97.8.2434 |
| PII | S0006-4971(20)55768-6 |
| PMID | 11290608 |
| MeSH | Acute Disease Amino Acid Substitution* Animals Aspartic Acid / chemistry COS Cells Cell Division Cell Line Cell Transformation, Neoplastic / genetics Chlorocebus aethiops Codon / genetics DNA, Complementary / genetics Hematologic Neoplasms / genetics* Humans Leukemia, Myeloid / genetics Mutagenesis, Site-Directed Mutation, Missense* Myelodysplastic Syndromes / genetics* Point Mutation* Protein Structure, Tertiary Proto-Oncogene Proteins / chemistry Proto-Oncogene Proteins / genetics* Receptor Protein-Tyrosine Kinases / chemistry Receptor Protein-Tyrosine Kinases / genetics* Recombinant Fusion Proteins / physiology Tandem Repeat Sequences Transfection fms-Like Tyrosine Kinase 3 |
| IF | 17.794 |
| Times Cited | 839 |
| WOS Category | HEMATOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 96 |
| Altmetric score changes over past 6months | 3.0 |
| Resource | |
| Human and Animal Cells | 32D(RCB1145) |