Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
Författare
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)
Avdelning/ar
- Stamcellscentrum (SCC)
- Institutionen för translationell medicin
- Avdelningen för molekylär hematologi
- Lymfocytutveckling och reglering
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publiceringsår
2011
Språk
Engelska
Sidor
3613-3621
Publikation/Tidskrift/Serie
Blood
Volym
118
Issue
13
Dokumenttyp
Artikel i tidskrift
Förlag
American Society of Hematology
Ämne
- Hematology
Status
Published
Forskningsgrupp
- Lymphoid Development and Regulation
ISBN/ISSN/Övrigt
- ISSN: 1528-0020