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

Journal article

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.

Authors: Kharazi, S; Mead, A; Mansour, A; Hultquist, A; Böiers, C

• Publication status: Published
• Journal: Blood
• Volume: 118
• Issue: 13
• Pages: 3613-3621
• Publication date: 2011-09-01
• DOI: 10.1182/blood-2010-06-289207
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Membrane Proteins; Cells, Cultured; Tandem Repeat Sequences; Animals; fms-Like Tyrosine Kinase 3; Mice, Transgenic; Loss of Heterozygosity; Mice, Inbred C57BL; Male; Gene Dosage; Cell Proliferation; Phenotype; Gene Knock-In Techniques; Myeloproliferative Disorders; Gene Duplication; Alleles; Bone Marrow Cells; Mice