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.

FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia

“…FLT3/FLT3-ITD activates SFK members such as Src, Lyn and Fyn, 26 – 28 and Src and Lyn can phosphorylate p27. 7 , 8 Phosphorylation of p27 by Src, however, also includes Y74, 8 but phosphorylation at this tyrosine was not detected in transfection assays ( Figure 2A , p27-Y88,89F), suggesting that Src is not the main tyrosine kinase that contributes to FLT3-ITD-induced p27 phosphorylation.…”

Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice

“…Genes that were differentially spliced in both mutant mouse strains and human samples included several genes implicated in the pathogenesis of myeloid malignancies; these include Csf3r, Fyn, Gnas, and Nsd1. [45][46][47][48][49] Among the CEs altered in both KSL and MP cells but not in human samples, approximately half had corresponding transcripts in the human orthologs; for those CEs, the frequency of CCNG motifs within the promoted CEs and GGNG motifs within the repressed CEs was decreased in human counterparts, which may in part account for the different splicing patterns between species ( Figure 7C).…”

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

“…Importantly, FLT3-ITD exhibited a higher Lyn binding affinity than FLT3-wild type (FLT3-WT), demonstrating the importance of Lyn in the proliferative FLT3-ITD signal transduction pathway [23]. Likewise, Fyn expression is differentially expressed in AML patient samples [26], and patients with both FLT3-ITD mutations and elevated Fyn expression exhibit inferior survival compared with patients with low Fyn expression [26]. Recently, Marhäll et al [28] demonstrated the cooperative role of the SFK member LCK in FLT3-ITD oncogenesis via enhancing FLT3-ITD mediated proliferative capacity and STAT5 phosphorylation.…”

“…Other kinases have been shown to be relevant to AML and to potentially cooperate with FLT3, such as the SFK [22][23][24][25][26]. Specifically, 76% of primary AML cells have increased Lyn kinase activity [27], and the inhibition of Lyn activity substantially reduced the growth of AML cell lines [24].…”