Mechanisms of STAT Protein Activation by Oncogenic KIT Mutants in Neoplastic Mast Cells

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

“…91 Finally, despite STAT1/3 activation, the expression levels of STAT5 seem to be critical for transcriptional regulation in HMC-1 and P815 MC lines, and for neoplastic cell growth and survival. 7 Altogether, these results strongly suggest that STAT5 is one major cellular effector in mastocytosis by controlling the mutant KIT-mediated aberrant growth signaling. However, the pharmacological inhibition of STAT5 remains challenging, and new STAT5 inhibitors active at pharmacological doses on both indolent and aggressive forms of SM are still needed.…”

“…4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs. 8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance.…”

“…84,85 Among the STAT proteins, particularly activated STAT5a/b proteins ( Figure 6) are thought to be of importance in MPNs, including SM and CML. 5,7 However, SM or CML are often slowly progressing diseases, and it is thus not surprising that there are cytoplasmic pathways that maintain high pSTAT5 levels in the cytoplasm. Direct docking of pSTAT5 via the scaffold molecule GAB2 to the regulatory p85 subunit of PI3K is a prominent mechanism of cytoplasmic retention (Figures 2 and 6).…”

Gene Expression Profiling of Human c-Kit Mutant D816V

“…A search for the genes regulated by D816V-c-Kit revealed up-regulation of genes involved in cellular proliferation including PIK3R1, FES, INSIG1, eIF4B; and mitogen-activated protein kinases (MAPK) signaling pathway genes, MAP2K3 and MAPK14. The constitutively activated D816V-c-Kit mutation leads to the recruitment of major pro-oncogenic signaling cascades, such as the PI3K signaling, STAT, or RAS/MAPK pathway [31]. Quantitative PCR validated upregulation of PIK3R1.…”

“…STAT5 up-regulation by mutant D816V-c-Kit expressing cells as downstream target is consistent with STAT5 up-regulation as downstream target in D816V-c-Kit expressing HMC-1 cells important for cell proliferation. STAT activation can be aberrant as it is involved with other pathological situations [31] [41]. The up-regulation of BCR/ABL in D816V-c-Kit expressing cells, which encodes for kinase active fusion protein, opens the possibility that mutant D816V phosphorylates additional substrate molecules that are not phosphorylated by wild-type c-Kit and is expected to constitute novel targets for selective therapy.…”