Journal
BLOOD
Volume 118, Issue 13, Pages 3613-3621Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-06-289207
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Funding
- EuroCancerStemCell
- EU
- Swedish Cancer Society
- Avtal om Lakerutbildning och Forskning (Government Public Health)
- Region Skane
- Goran Gustafsson's Foundation
- Hemato-Linne (Swedish Research Council)
- Torsten och Ragnar Soderbergs Foundation
- Medical Research Council, United Kingdom
- Swedish Pediatric Cancer Foundation
- Pasteur Institute of Iran
- Leukemia and Lymphoma Research
- Medical Research Council [G84/6443, G0801073, G0701761, G0900892, G0700711B] Funding Source: researchfish
- MRC [G84/6443, G0900892, G0701761, G0801073] Funding Source: UKRI
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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. (Blood. 2011; 118(13):3613-3621)
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