Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice

Clinical evidence has shown that FLT3 internal tandem duplication (ITD) mutation confers poor prognosis in acute myeloid leukemia. Loss of the FLT3 wildtype (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. (Blood. 2011;118(18):4935-4945)