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Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.

Original publication

DOI

10.1016/j.ccr.2007.08.031

Type

Journal article

Journal

Cancer Cell

Publication Date

10/2007

Volume

12

Pages

367 - 380

Keywords

Animals, Cell Differentiation, Cell Proliferation, Cell Survival, Cells, Cultured, Exons, Gene Expression Regulation, Neoplastic, Genotype, Hematopoietic Stem Cells, Humans, Kaplan-Meier Estimate, Leukemia, Experimental, Leukemia, Myelomonocytic, Chronic, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Multipotent Stem Cells, Mutation, Myeloproliferative Disorders, Phenotype, Signal Transduction, fms-Like Tyrosine Kinase 3