Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
Author
Summary, in English
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)
Department/s
- Stem Cell Center
- Department of Translational Medicine
- Division of Molecular Hematology (DMH)
- Lymphoid Development and Regulation
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2011
Language
English
Pages
3613-3621
Publication/Series
Blood
Volume
118
Issue
13
Document type
Journal article
Publisher
American Society of Hematology
Topic
- Hematology
Status
Published
Research group
- Lymphoid Development and Regulation
ISBN/ISSN/Other
- ISSN: 1528-0020