title: FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model.
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.
authors.affiliation: Division of Hematology/Oncology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Christina L
authors.initials: CL
authors.lastname: Boulton
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D007964:Leukocytosis; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D013163:Splenomegaly; D020080:Tandem Repeat Sequences; D014162:Transfection; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1
chemical_list: D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1