中国

Publications

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD–induced myeloproliferation

Kharazi, S., Mead, A.J., Mansour, A., Hultquist, A., Boiers, C., Luc, S., Buza-Vidas, N., Ma, Z., Ferry, H., Atkinson, D., et al

Acquisition of homozygous activating growth factor receptor 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 knockin 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 LinSca1+c-Kit+ 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 demonstrate here that the mouse Flt3ITD/ITD myeloid phenotype is FLT3 ligand-independent.

Citation

Kharazi, S., Mead, A.J., Mansour, A., Hultquist, A., Boiers, C., Luc, S., Buza-Vidas, N., Ma, Z., Ferry, H., Atkinson, D., et al "Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD–induced myeloproliferation" Blood (2011): 3,613–21