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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 Lin(-)Sca1(+)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 Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.

Original publication

DOI

10.1182/blood-2010-06-289207

Type

Journal article

Journal

Blood

Publication Date

29/09/2011

Volume

118

Pages

3613 - 3621

Keywords

Alleles, Animals, Bone Marrow Cells, Cell Proliferation, Cells, Cultured, Gene Dosage, Gene Duplication, Gene Knock-In Techniques, Loss of Heterozygosity, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myeloproliferative Disorders, Phenotype, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3