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 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.
ASJC Scopus subject areas
- Cell Biology