Impact of gene dosage, loss of wild type allele and FLT3 ligand on Flt3-ITD induced myeloproliferation.
Nummer: Aug 2
Acquisition of homozygous activating growth factor receptor (GFR) mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knock-in model of Flt3-internal tandem duplication (Flt3-ITD) induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) (LSK) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we here demonstrate that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand independent.
- Medicine and Health Sciences
- ISSN: 1528-0020