title: Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.
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. FLT3wt/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 FLT3wt/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 FLT3wt/ITD mice showed enhanced potential to generate myeloid colonies in vitro. BM from FLT3wt/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 FLT3wt/ITD mice outgrew 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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Obdulio
authors.initials: O
authors.lastname: Piloto
authors.forename: Ho Bao
authors.initials: HB
authors.lastname: Nguyen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Greenberg
authors.forename: Kogo
authors.initials: K
authors.lastname: Takamiya
authors.forename: Frederick
authors.initials: F
authors.lastname: Racke
authors.forename: David
authors.initials: D
authors.lastname: Huso
authors.forename: Donald
authors.initials: D
authors.lastname: Small
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D007964:Leukocytosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3