FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model.
Activating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in approximately 30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6-12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3.
Lee
Benjamin H
BH
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Williams
Ifor R
IR
Anastasiadou
Ema
E
Boulton
Christina L
CL
Joseph
Sarah W
SW
Amaral
Sonia M
SM
Curley
David P
DP
Duclos
Nicole
N
Huntly
Brian J P
BJ
Fabbro
Doriano
D
Griffin
James D
JD
Gilliland
Dwight Gary
DG
D000818:Animals; D004195:Disease Models, Animal; D020440:Gene Duplication; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000503:physiopathology; D008223:Lymphoma / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000502:physiology
C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin