title: FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bhlee@partners.org
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: McDowell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adelsperger
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Miloslav
authors.initials: M
authors.lastname: Beran
authors.forename: Sten Eirik
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3