title: FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia.
abstract: FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases, which are frequently over-expressed in human cancers, and play key roles in cancer biology. SRC has long been recognized as an important oncogene, but little attention has been given to its other family members. In this report, we have studied the role of FYN in FLT3 signaling in respect to acute myeloid leukemia (AML). We observed that FYN displays a strong association with wild-type FLT3 as well as oncogenic FLT3-ITD and is dependent on the kinase activity of FLT3 and the SH2 domain of FYN. We identified multiple FYN binding sites in FLT3, which partially overlapped with SRC binding sites. To understand the role of FYN in FLT3 signaling, we generated FYN overexpressing cells. We observed that expression of FYN resulted in slightly enhanced phosphorylation of AKT, ERK1/2 and p38 in response to ligand stimulation. Furthermore, FYN expression led to a slight increase in FLT3-ITD-dependent cell proliferation, but potent enhancement of STAT5 phosphorylation as well as colony formation. We also observed that FYN expression is deregulated in AML patient samples and that higher expression of FYN, in combination with FLT3-ITD mutation, resulted in enrichment of the STAT5 signaling pathway and correlated with poor prognosis in AML. Taken together our data suggest that FYN cooperates with oncogenic FLT3-ITD in cellular transformation by selective activation of the STAT5 pathway. Therefore, inhibition of FYN, in combination with FLT3 inhibition, will most likely be beneficial for this group of AML patients.
authors: Division of Translational Cancer Research, and Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors: Rohit A
authors: RA
authors: Chougule
authors: Division of Translational Cancer Research, and Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors: Julhash U
authors: JU
authors: Kazi
authors: Division of Translational Cancer Research, and Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors: Lars
authors: L
authors: Rönnstrand
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011379:Prognosis; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050799:STAT5 Transcription Factor; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn
keywords: FLT3; FLT3-ITD; FYN; STAT5; acute myeloid leukemia