Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model

Li Li, Obdulio Piloto, Ho Bao Nguyen, Kathleen Greenberg, Kogo Takamiya, Frederick Racke, David Huso, Donald Small

Research output: Contribution to journalArticlepeer-review

Abstract

Constitutive activation of FMS-like tyrosine kinase 3 (FLT3) by internal tandem duplication (ITD) mutations is one of the most common molecular alterations known in acute myeloid leukemia (AML). To investigate the role FLT3/ITD mutations play in the development of leukemia, we generated a FLT3/ITD knock-in mouse model by inserting an ITD mutation into the juxtamembrane domain of murine Flt3. FLT3 wt/ITD mice developed myeloproliferative disease, characterized by splenomegaly, leukocytosis, and myeloid hypercellularity, which progressed to mortality by 6 to 20 months. Bone marrow (BM) and spleen from FLT3 wt/ITD mice had an increased fraction of granulocytes/monocytes and dendritic cells, and a decreased fraction of B-lymphocytes. No sign of acute leukemia was observed over the lifetime of these mice. BM from FLT3 wt/ITD mice showed enhanced potential to generate myeloid colonies in vitro. BM from FLT3 wt/ITD mice also produced more spleen colonies in the in vivo colony-forming unit (CFU)-spleen assay. In the long-term competitive repopulation assay, BM cells from FLT3 wt/ITD mice out-grew the wild-type competitor cells and showed increased myeloid and reduced lymphoid expansion activity. In summary, our data indicate that expression of FLT3/ITD mutations alone is capable of conferring normal hematopoietic stem/progenitor cells (HSPCs) with enhanced myeloid expansion. It also appears to suppress B lymphoid maturation. Additional cooperative events appear to be required to progress to acute leukemia.

Original languageEnglish (US)
Pages (from-to)3849-3858
Number of pages10
JournalBlood
Volume111
Issue number7
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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