FES kinases are required for oncogenic FLT3 signaling

E Voisset; S Lopez; A Chaix; C Georges; K Hanssens; T Prébet; P Dubreuil; P De Sepulveda

doi:10.1038/leu.2009.301

FES kinases are required for oncogenic FLT3 signaling

Leukemia. 2010 Apr;24(4):721-8. doi: 10.1038/leu.2009.301. Epub 2010 Jan 28.

Authors

E Voisset¹, S Lopez, A Chaix, C Georges, K Hanssens, T Prébet, P Dubreuil, P De Sepulveda

Affiliation

¹ INSERM, UMR 891, Centre de Recherche en Cancérologie de Marseille, Laboratoire de Signalisation, Hématopoïèse et Mécanismes de l'Oncogenèse, Marseille, France.

PMID: 20111072
DOI: 10.1038/leu.2009.301

Abstract

The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blotting, Western
Cell Cycle
Cell Proliferation
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Immunoprecipitation
Inverted Repeat Sequences / genetics*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology
Mutation / genetics
Phosphorylation
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins c-fes / antagonists & inhibitors
Proto-Oncogene Proteins c-fes / genetics
Proto-Oncogene Proteins c-fes / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction*
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism*

Substances

RNA, Messenger
RNA, Small Interfering
proto-oncogene protein c-fes-fps
FLT3 protein, human
Protein-Tyrosine Kinases
fms-Like Tyrosine Kinase 3
FES protein, human
Proto-Oncogene Proteins c-fes