TY - JOUR
T1 - Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice
AU - Li, Li
AU - Bailey, Emily
AU - Greenblatt, Sarah
AU - Huso, David L
AU - Small, Donald
PY - 2011/11/3
Y1 - 2011/11/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80855133514&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80855133514&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-01-328096
DO - 10.1182/blood-2011-01-328096
M3 - Article
C2 - 21908433
AN - SCOPUS:80855133514
SN - 0006-4971
VL - 118
SP - 4935
EP - 4945
JO - Blood
JF - Blood
IS - 18
ER -