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FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia.

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.

Pubmed ID: 17936561

Authors

  • Lee BH
  • Tothova Z
  • Levine RL
  • Anderson K
  • Buza-Vidas N
  • Cullen DE
  • McDowell EP
  • Adelsperger J
  • Fröhling S
  • Huntly BJ
  • Beran M
  • Jacobsen SE
  • Gilliland DG

Journal

Cancer cell

Publication Data

October 15, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA105423
  • Agency: NCI NIH HHS, Id: CA113434
  • Agency: NCI NIH HHS, Id: CA66996
  • Agency: Medical Research Council, Id: G0501838
  • Agency: Medical Research Council, Id: G116/187
  • Agency: NCI NIH HHS, Id: K08 CA113434-01A1
  • Agency: NCI NIH HHS, Id: K08 CA113434-02
  • Agency: NCI NIH HHS, Id: P01 CA066996
  • Agency: NCI NIH HHS, Id: P01 CA066996-100001
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • 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