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 FLT3wt/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 (FLT3ITD/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 FLT3wt/ITD mice. Reintroduction of the WT FLT3 allele into FLT3−/ITD BM slowed the progression of MPN in recipient mice. FLT3ITD/ITD mice had an even severe MPN compared with the FLT3−/ITD and FLT3wt/ITD mice. Spontaneous leukemia developed in a small fraction of the FLT3ITD/ITD mice but was never observed in the FLT3−/ITD and FLT3wt/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.