Critical Role of STAT5 Activation in Transformation Mediated by ZNF198-FGFR1

Abstract

The 8p11 myeloproliferative syndrome is an aggressive disorder caused by FGFR1 fusion proteins resulting from a subset of acquired translocations that target chromosome band 8p11. These chimeric proteins have constitutive FGFR1 tyrosine kinase activity and are believed to deregulate hemopoietic development in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here we have studied the role of STAT proteins in transformation mediated by the most common of these fusions, ZNF198-FGFR1. We found that STATs 1, 3, and 5 were activated constitutively in ZNF198-FGFR1-transformed Ba/F3 cells and that STATs 2, 4, and 6 were also tyrosine-phosphorylated. Induction of dominant negative STAT mutants showed that activation of STAT5, but not STATs 1 or 3, was essential for the anti-apoptotic effect of ZNF198-FGFR1 and that STAT5 activation is essential for the elevated levels of BclXL in transformed cells. STAT5 activation was also shown to be required for continued cell cycle progression of BaF3/ZNF198-FGFR1 cells in conditions of cytokine deprivation and for up-regulation of the DNA repair protein Rad51. These findings suggest a critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1.

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

“…Whereas STAT1 is clearly known to trigger apoptosis, STAT3 seems to have proapoptotic or antiapoptotic effects depending on the cell type (Chapman et al, 1999;Stephanou et al, 2000;Battle and Frank, 2002). Most of the studies about STAT5 described it as an anti-apoptotic factor, leading to oncogenesis when activated (Battle and Frank, 2002;Debierre-Grockiego, 2004;Heath and Cross, 2004). Nevertheless, hyperphosphorylation of STAT5 after IL-3 treatment was shown to induce apoptosis on myeloid cells expressing a constitutively active STAT5 mutant.…”

Fusion tyrosine kinases: a result and cause of genomic instability

“…Elevated levels of RAD51 have been observed in various tumors and positively associated with genotoxic therapy resistance (Vispe et al, 1998;Collis et al, 2001;Raderschall et al, 2002;Slupianek et al, 2002Slupianek et al, , 2006. Leukemias and lymphomas expressing BCR/ABL-related FTKs, such as TEL/ABL, TEL/ PDGFbR, TEL/JAK2, NPM/ALK and ZNF198/ FGFR1, display elevated levels of RAD51 and enhanced HRR activity (Slupianek et al, , 2002Heath and Cross, 2004). Although Deutsch et al (2001) indicated that DNA-PKcs, an important kinase in NHEJ, may be downregulated in CML cells, subsequent reports employing various in vitro and in vivo methods detected enhanced activity of NHEJ in BCR/ABLtransformed leukemia cells and CML patient cells (Gaymes et al, 2002;Brady et al, 2003;Nowicki et al, 2004;Slupianek et al, 2006).…”

Analysis of transcriptional modulation of the presenilin 1 gene promoter by ZNF237, a candidate binding partner of the Ets transcription factor ERM

“…Hence it has been inferred that the fusion proteins themselves may lead to the abnormal phenotypes likely by oligomerization of the fusion protein leading to constitutive activation of the receptor [2,35]. Indeed, the fusion ZNF198-FGFR1 (fibroblast growth factor receptor 1) is observed in a stem cell myeloproliferative disorder [34] and it has been shown that the fusion protein by itself increases the resistance of Ba/F3 cells to apoptosis and their ability to progress through cell cycle in the absence of serum or cytokines characteristic of transformed cells [1,13]. The Cterminal proline rich region rather than the zinc finger appears to be required for oligomerization, downstream signaling activity and transformation [2,35].…”

“…ZNF198 itself appears to have the ability to interact with proteins associated with DNA repair, replication and chromosomal segregation [17] and this may enable it to affect these cellular pathways [13]. The acidic N-terminal domain of ZNF198 is largely homologous to ZNF237.…”