Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model.
Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sarah
S
Greenblatt
Li
L
Li
Christopher
C
Slape
Bao
B
Nguyen
Rachel
R
Novak
Amy
A
Duffield
David
D
Huso
Stephen
S
Desiderio
Michael J
MJ
Borowitz
Peter
P
Aplan
Donald
D
Small
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C099959:homeobox protein HOXA13; C093350:nuclear pore complex protein 98; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3