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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wu, Chuan-feng Mi, Jian-qing Ren, Ruibao Liang, Yang Xiong, Shu-min Chen, Sai-juan Shi, Lin Chen, Zhu Wang, Yue-ying Liu, Ping Zhao, Li-juan |
| Description | Author Affiliation: Wang YY ( State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.); |
| Abstract | The full-length AML1-ETO (AE) fusion gene resulting from t(8;21)(q22;q22) in human acute myeloid leukemia (AML) is not sufficient to induce leukemia in animals, suggesting that additional mutations are required for leukemogenesis. We and others have identified activating mutations of C-KIT in nearly half of patients with t(8;21) AML. To test the hypothesis that activating C-KIT mutations cooperate with AE to cause overt AML, we generated a murine transduction and transplantation model with both mutated C-KIT and AE. To overcome the intracellular transport block of human C-KIT in murine cells, we engineered hybrid C-KIT (HyC-KIT) by fusing the extracellular and transmembrane domains of the murine c-Kit in-frame to the intracellular signaling domain of human C-KIT. We showed that tyrosine kinase domain mutants HyC-KIT N822K and D816V, as well as juxtamembrane mutants HyC-KIT 571+14 and 557-558Del, could transform murine 32D cells to cytokine-independent growth. The protein tyrosine kinase inhibitor dasatinib inhibited the proliferation of 32D cells expressing these C-KIT mutants, with potency in the low nanomolar range. In mice, HyC-KIT N822K induced a myeloproliferative disease, whereas HyC-KIT 571+14 induces both myeloproliferative disease and lymphocytic leukemia. Interestingly, coexpression of AE and HyC-KIT N822K led to fatal AML. Our data have further enriched the two-hit model that abnormalities of both transcription factor and membrane/cytosolic signaling molecule are required in AML pathogenesis. Furthermore, dasatinib prolonged lifespan of mice bearing AE and HyC-KIT N822K-coexpressing leukemic cells and exerted synergic effects while combined with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 6 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Transformation, Neoplastic Core Binding Factor Alpha 2 Subunit Leukemia, Myeloid, Acute Mutation Oncogene Proteins, Fusion Proto-Oncogene Proteins C-kit Animals Antimetabolites, Antineoplastic Pharmacology Genetics Metabolism Pathology Chromosomes, Human, Pair 21 Chromosomes, Human, Pair 8 Cytarabine Leukemia, Lymphoid Mice Mice, Transgenic NIH 3T3 Cells Protein Structure, Tertiary Translocation, Genetic Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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