title: Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice.
abstract: Clinical evidence has shown that FLT3 internal tandem duplication (ITD) mutation confers poor prognosis in acute myeloid leukemia. Loss of the FLT3 wild-type (WT) allele is associated with even worse prognosis. We have previously reported that heterozygous FLT3(wt/ITD) "knockin" mice develop a slowly fatal myeloproliferative neoplasm (MPN). To study the roles of the WT FLT3 and ITD alleles in the development of MPNs, we generated FLT3/ITD homozygous (FLT3(ITD/ITD)) and hemizygous (FLT3(-/ITD)) mice. FLT3(-/ITD) mice, with the loss of WT allele, display a more severe MPN, as evidenced by even larger spleen, higher white blood cell counts, and shorter survival, compared with FLT3(wt/ITD) mice. Reintroduction of the WT FLT3 allele into FLT3(-/ITD) BM slowed the progression of MPN in recipient mice. FLT3(ITD/ITD) mice had an even severe MPN compared with the FLT3(-/ITD) and FLT3(wt/ITD) mice. Spontaneous leukemia developed in a small fraction of the FLT3(ITD/ITD) mice but was never observed in the FLT3(-/ITD) and FLT3(wt/ITD) mice. Our results suggest that loss of the WT allele contributes to the development of a more severe phenotype. Thus, the WT FLT3 allele seemingly functions as a tumor suppressor, attenuating the function of the FLT3/ITD allele in leukemia harboring FLT3/ITD mutations.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Li
authors: L
authors: Li
authors: Emily
authors: E
authors: Bailey
authors: Sarah
authors: S
authors: Greenblatt
authors: David
authors: D
authors: Huso
authors: Donald
authors: D
authors: Small
mesh_terms: D000483:Alleles; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D019656:Loss of Heterozygosity / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D020080:Tandem Repeat Sequences / Q000235:genetics / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3