title: Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation.
abstract: Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.
authors.affiliation: Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University Biomedical Center, Lund, Sweden.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Kharazi
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Anna
authors.initials: A
authors.lastname: Mansour
authors.forename: Anne
authors.initials: A
authors.lastname: Hultquist
authors.forename: Charlotta
authors.initials: C
authors.lastname: Böiers
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ma
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.forename: Debbie
authors.initials: D
authors.lastname: Atkinson
authors.forename: Kristian
authors.initials: K
authors.lastname: Reckzeh
authors.forename: Kristina
authors.initials: K
authors.lastname: Masson
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.forename: Fumio
authors.initials: F
authors.lastname: Arai
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.forename: Ewa
authors.initials: E
authors.lastname: Sitnicka
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000483:Alleles; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018628:Gene Dosage / Q000502:physiology*; D020440:Gene Duplication / Q000502:physiology*; D055879:Gene Knock-In Techniques; D019656:Loss of Heterozygosity / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010641:Phenotype; D020080:Tandem Repeat Sequences / Q000235:genetics / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3