title: FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice.
abstract: FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately one third of acute myeloid leukemia cases. The most common FLT3 mutations in acute myeloid leukemia are internal tandem duplication (ITD) mutations in the juxtamembrane domain (23%) and point mutations in the tyrosine kinase domain (10%). The mutation substituting the aspartic acid at position 838 (equivalent to the human aspartic acid residue at position 835) with a tyrosine (referred to as FLT3/D835Y hereafter) is the most frequent kinase domain mutation, converting aspartic acid to tyrosine. Although both of these mutations constitutively activate FLT3, patients with an ITD mutation have a significantly poorer prognosis. To elucidate the mechanisms behind this prognostic difference, we have generated a knock-in mouse model with a D838Y point mutation in FLT3 that corresponds to the FLT3/D835Y mutation described in humans. Compared with FLT3/ITD knock-in mice, the FLT3/D835Y knock-in mice survive significantly longer. The majority of these mice develop myeloproliferative neoplasms with a less-aggressive phenotype. In addition, FLT3/D835Y mice have distinct hematopoietic development patterns. Unlike the tremendous depletion of the hematopoietic stem cell compartment we have observed in FLT3/ITD mice, FLT3/D835Y mutant mice are not depleted in hematopoietic stem cells. Further comparisons of these FLT3/D835Y knock-in mice with FLT3/ITD mice should provide an ideal platform for dissecting the molecular mechanisms that underlie the prognostic differences between the two different types of FLT3 mutations.
authors.affiliation: Departments of Oncology, Pathology, and Pediatrics, The Johns Hopkins School of Medicine, Baltimore, MD 21231.
authors.forename: Emily
authors.initials: E
authors.lastname: Bailey
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Amy S
authors.initials: AS
authors.lastname: Duffield
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ma
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Don
authors.initials: D
authors.lastname: Small
mesh_terms: D000818:Animals; D055879:Gene Knock-In Techniques / Q000379:methods*; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D023421:Models, Animal; D020125:Mutation, Missense / Q000235:genetics; D011379:Prognosis; D056916:Segmental Duplications, Genomic / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3