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

TitleImpact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation.
Publication TypeJournal Article
Year of Publication2011
AuthorsKharazi S, Mead AJ, Mansour A, Hultquist A, Böiers C, Luc S, Buza-Vidas N, Ma Z, Ferry H, Atkinson D, Reckzeh K, Masson K, Cammenga J, Rönnstrand L, Arai F, Suda T, Nerlov C, Sitnicka E, Jacobsen SEirik W
JournalBlood
Volume118
Issue13
Pagination3613-21
Date Published2011 Sep 29
ISSN1528-0020
KeywordsAlleles, Animals, Bone Marrow Cells, Cell Proliferation, Cells, Cultured, fms-Like Tyrosine Kinase 3, 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
Abstract

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.

DOI10.1182/blood-2010-06-289207
Alternate JournalBlood
PubMed ID21813452
Grant ListG0501838 / / Medical Research Council / United Kingdom
G0801073 / / Medical Research Council / United Kingdom
G0900892 / / Medical Research Council / United Kingdom