Further activation of FLT3 mutants by FLT3 ligand
Open Access
- 25 April 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 30 (38), 4004-4014
- https://doi.org/10.1038/onc.2011.110
Abstract
Somatic mutations of FLT3 involving internal tandem duplication (ITD) of the juxtamembrane domain or point mutations in the tyrosine kinase domain (TKD) appear to activate FLT3 in a FLT3 ligand (FL)-independent manner. To determine whether or not FLT3 mutants respond to FL for their activation, a FL-deficient (FL−/−) murine embryo fibroblast (MEF) cell line was established. Expression of FLT3/ITD and FLT3/TKD mutations in FL−/− MEF cells resulted in low levels of constitutive phosphorylation of FLT3. However, a more than fourfold increase of FLT3 autophosphorylation was induced by exogenous FL. Rescue of endogenous FL expression in FL−/− MEF cells expressing FLT3 mutants led to more than a threefold increase of FLT3 phosphorylation. FL addition led to further activation of the FLT3 receptors and enhanced survival and/or decreased apoptosis in leukemia-derived cell lines and primary leukemic cells expressing FLT3 mutations. Functional studies revealed that exogenous FL promoted the colony-forming and recloning abilities of FLT3 mutant transduced primary bone marrow cells derived from FL−/− mice. Endogenous FL contributes in vivo to functional signaling through FLT3 as noted by the decreased survival of FL+/+ITD+/+ mice compared with FL−/−ITD+/+ mice. These data suggest that FL leads to further activation of FLT3 mutants and is especially important in light of recent findings of elevated FL levels in acute myeloid leukemia patients in response to chemotherapy.Keywords
This publication has 45 references indexed in Scilit:
- Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapseBlood, 2011
- FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivoBlood, 2011
- Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse modelBlood, 2008
- Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibodyBlood, 2004
- Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutationsBlood, 2002
- Genomic structure of human FLT3: implications for mutational analysisBritish Journal of Haematology, 2001
- Flt3 Ligand Induces Tyrosine Phosphorylation of Gab1 and Gab2 and Their Association with Shp-2, Grb2, and PI3 KinaseBiochemical and Biophysical Research Communications, 2000
- Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemiaLeukemia, 1999
- Molecular cloning of a ligand for the flt3flk-2 tyrosine kinase receptor: A proliferative factor for primitive hematopoietic cellsCell, 1993
- Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.JCI Insight, 1993