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| FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model |
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| Author(s): Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG |
| Source: BLOOD Volume: 99 Issue: 1 Pages: 310-318 Published: JAN 1 2002 |
| Times Cited: 231 References: 74 |
| Abstract: FLT3 receptor tyrosine kinase is expressed on lymphoid and myeloid progenitors in the hematopoietic system. Activating mutations in FLT3 have been identified in approximately 30% of patients with acute myelogenous leukemia, making it one of the most common mutations observed in this disease. Frequently, the mutation is an in-frame internal tandem duplication (ITD) in the juxtamembrane region that results in constitutive activation of FLT3, and confers interleukin-3 (IL-3)-independent growth to Ba/F3 and 32D cells. FLT3-ITD mutants were cloned from primary human leukemia samples and assayed for transformation of primary hematopoietic cells using a murine bone marrow transplantation assay. FLT3-ITDs induced an oligoclonal myeloproliferative disorder in mice, characterized by splenomegaly and leukocytosis. The myeloproliferative phenotype, which was associated with extramedullary hematopoiesis in the spleen and liver, was confirmed by histopathologic and flow cytometric analysis. The disease latency of 40 to 60 days with FLT3-ITDs contrasted with wild-type FLT3 and enhanced green fluorescent protein (EGFP) controls, which did not develop hematologic disease (> 200 days). These results demonstrate that FLT3-ITD mutant proteins are sufficient to induce a myeloproliferative disorder, but are insufficient to recapitulate the AML phenotype observed in humans. Additional mutations that impair hematopoietic differentiation may be required for the development of FLT3-ITD-associated acute myeloid leukemias. This model system should be useful to assess the contribution of additional cooperating mutations and to evaluate specific FLT3 inhibitors in vivo. (Blood. 2002;99: 310-318) 2002 by The American Society of Hematology. |
| Document Type: Article |
| Language: English |
| Reprint Address: Gilliland, DG (reprint author), Harvard Univ, Inst Med, 4 Blackfan Cir,Rm 418, Boston, MA 02115 USA |
Addresses:
1. Brigham & Womens Hosp, Dept Pathol, Div Haematol Oncol, Boston, MA 02115 USA
2. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA
3. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA |
| Publisher: AMER SOC HEMATOLOGY, 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA |
| Subject Category: Hematology |
| IDS Number: 506PK |
| ISSN: 0006-4971 |
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