Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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The t(8;13)(p11;q12) is the most common translocation associated with the 8p11 myeloproliferative syndrome and results in an identical mRNA fusion between ZNF198 at 13q12 and FGFR1 at 8p11 in all cases thus far reported. ZNF198 is a widely expressed gene that is predicted to encode a 1377-amino-acid protein with five Zn finger-related motifs known as MYM domains. To determine the genomic DNA structure of ZNF198, we employed bubble PCR from PAC clones with a panel of gene-specific primers. Sequencing of these products revealed that ZNF198 consists of 26 exons with the initiation codon located in exon 4. The t(8;13) results in a consistent mRNA fusion of ZNF198 exon 17 to FGFR1 exon 9. Notable features of the structure of ZNF198 include three noncanonical GC donor splice sites and the presence of an alternatively spliced intron within exon 4. Amplification of genomic DNA from six t(8;13) patients with primers to ZNF198 exon 17 and FGFR1 exon 9 yielded patient-specific products ranging in size from 500 bp to 2.5 kb, indicating that the positions of the breakpoints in the t(8;13) are tightly clustered. The positions of the six t(8;13) breakpoints were determined and found to be distributed across ZNF198 intron 17 and FGFR1 intron 8 with no apparent subclustering. No consistent sequence motifs, repeats, or topoisomerase II cleavage sites were found at or near the breakpoints. It remains unclear why the t(8;13) translocation breakpoints occur within such small genomic regions, and it is possible that strict ZNF198-FGFR1 coding requirements restrict the positions of the breakpoints.
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PMID:The genomic structure of ZNF198 and location of breakpoints in the t(8;13) myeloproliferative syndrome. 988 6

In patients with an atypical stem-cell myeloproliferative disorder with lymphoma (B or T cell), myeloid hyperplasia, and eosinophilia, the chromosome 8p11-12 region is the site of a recurrent breakpoint that can be associated with three different partners, 6q27, 9q32-34, and 13q12. Rearrangements are supposed to affect a pluripotent stem cell capable of myeloid and lymphoid differentiation and to involve the same 8p11-12 gene. The t(8;13) translocation has recently been shown to result in a fusion between the FGFR1 gene that encodes a tyrosine kinase receptor for fibroblast growth factors and a novel gene, FIM (also called RAMP or ZNF198), belonging to a novel family of zinc finger genes. In the present study, we have cloned the t(6;8)(q27;p11) translocation in two patients and found a fusion between FGFR1 and a novel gene, FOP (FGFR1 Oncogene Partner), located on chromosome band 6q27. This gene is alternatively spliced and ubiquitously expressed. It encodes a protein containing two regions of putative leucine-rich repeats putatively folding in alpha-helices and separated by a hydrophobic spacer. The two reciprocal fusion transcripts were evidenced by reverse transcription-polymerase chain reaction in the tumoral cells of the patients. The predicted chimeric FOP-FGFR1 protein contains the FOP N-terminus leucine-rich region fused to the catalytic domain of FGFR1. It may promote hematopoietic stem cell proliferation and leukemogenesis through a constitutive phosphorylation and activation of the downstream pathway of FGFR1.
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PMID:The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. 994 82

A 40-year-old male patient presented with leukocytosis and mild splenomegaly. Bone marrow aspirate showed myeloid hyperplasia and eosinophilia resembling chronic myelogenous leukemia in the chronic phase. Cytogenetic examination of bone marrow cells revealed an unusual karyotype, t(8;13)(p11;q12), in 20/20 metaphases. Not the BCR/ABL, but the ZNF198/FGFR1 chimeric mRNA was detected by reverse transcription-polymerase chain reaction. Since 1992, 12 patients with a similar atypical myeloproliferative disorder with T-cell non-Hodgkin's lymphoma or eosinophilia, associated with a t(8;13) translocation in both bone marrow and lymph node specimens, have been described. The present case is an additional one that should be classified into this new clinicopathologic entity.
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PMID:A chronic myelogenous leukemia-like myeloproliferative disorder accompanied by T-cell lymphoblastic lymphoma with chromosome translocation t(8;13)(p11;q12): a Japanese case. 1064 54

An acquired chromosomal translocation, t(8;13)(p11;q11-12), observed in a distinctive type of stem cell leukemia/lymphoma syndrome, leads to the fusion of the 5' portion of ZNF198 and the 3' portion of FGFR1. ZNF198-FGFR1 fusion transcripts encode 4 to 10 zinc fingers, a proline-rich region, and the intracellular portion of the FGFR1 (fibroblast growth factor receptor 1) receptor tyrosine kinase. We demonstrate that the ZNF198 proline-rich region constitutes a novel self-association domain. When fused to the intracellular domain of FGFR1, the ZNF198 proline-rich region is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3 independent growth. (Blood. 2000;96:699-704)
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PMID:ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain. 1088 37

The ZNF198- FGFR1 fusion gene arises as a result of the t(8;13)(p11;q12) in the 8p11 myeloproliferative syndrome. To determine the transforming properties of this chimeric protein we transfected ZNF198-FGFR1 into the interleukin (IL)-3 dependent cell line Ba/F3. Growth factor independent subclones were obtained in which ZNF198-FGFR1, STAT1, and STAT5 were constitutively tyrosine phosphorylated, as determined by immunoprecipitation and Western blot analysis. To test the hypothesis that constitutive activation of ZNF198-FGFR1 tyrosine kinase activity is a result of self-association of the fusion protein, we in vitro transcribed and translated ZNF198-FGFR1 and a derivative construct, ZNF198- FGFR1deltaC-myc, in which the C-terminal FGFR1 epitope was replaced by a c-myc tag. As expected, an anti-FGFR1 antibody immunoprecipitated ZNF198-FGFR1 but not ZNF198-FGFRdeltaC-myc. However when both products were translated together, both were coimmunoprecipitated by anti-FGFR1 antisera. Similar results were obtained by using an anti-myc antibody and demonstrated a physical interaction between the two proteins. Analysis of COS-7 cells transfected with ZNF198-FGFR1 demonstrated that the fusion gene, in contrast to normal FGFR1, is located in the cytoplasm. We conclude that ZNF198-FGFR1 is a cytoplasmic protein that self-associates and has constitutive transformation activity. These data suggest that ZNF198-FGFR1 plays a primary role in the pathogenesis of the t(8;13) myeloproliferative syndrome and is the first report to implicate STAT proteins in FGFR1-mediated signaling.
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PMID:ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. 1093 90

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.
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PMID:Identification of four new translocations involving FGFR1 in myeloid disorders. 1155 Feb 83

Several recurrent translocations that involve chromosome band 8p11 have been described in myeloid malignancies. These translocations target two distinct genes: (1) FGFR1, a receptor tyrosine kinase for fibroblast growth factors, and (2) MOZ, a putative histone acetyltransferase whose precise function remains to be defined. Disruption of FGFR1 is associated with a disease entity known as the 8p11 myeloproliferative syndrome (EMS)/stem cell leukemia-lymphoma syndrome, a chronic myeloproliferative disorder that frequently presents with eosinophilia and associated T-cell lymphoblastic lymphoma. The disease is aggressive and rapidly transforms to acute leukaemia, usually of myeloid phenotype. Currently, only allogeneic stem cell transplantation appears to be effective in eradicating or suppressing the malignant clone. To date, four gene fusions associated with distinct translocations have been described in EMS: the t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11q22) fuse ZNF198, CEP110, FOP and BCR, respectively, to FGFR1. The resulting fusion proteins have constitutive tyrosine kinase activity and activate multiple signal transduction pathways. These pathways and the fusion proteins are attractive targets for targeted signal transduction therapy.
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PMID:The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. 1191 91

A highly specific t(8;13)(p11;q12) translocation has been consistently identified in bone marrow cells from patients with an atypical myeloproliferative disease that is associated with peripheral blood eosinophila and T- or B-cell leukemias. In all patients analysed to date, the translocation event results in a chimeric gene in which the atypical zinc-finger domain of ZNF198 is fused to the N-terminal end of the catalytic domain of the FGFR1 receptor tyrosine kinase. To understand more about the consequences of this rearrangement we have investigated the normal function of the ZNF198 gene. Using yeast two-hybrid analysis we identified HHR6 as a protein binding partner and confirmed this using immunoprecipitation studies. The ZNF198/FGFR1 fusion protein also binds to HHR6. We demonstrate here that the human RAD18 is also present in the ZNF198/HHR6 protein complex, although it does not coimmunoprecipitate with the fusion kinase. Cells expressing the fusion kinase gene show a marked increased sensitivity to UVB irradiation, suggesting that it acts in a dominant-negative way to affect DNA repair. These observations support the idea that ZNF198, through its interaction with HHR6 and RAD18, may be involved in the DNA repair process.
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PMID:ZNF198 protein, involved in rearrangement in myeloproliferative disease, forms complexes with the DNA repair-associated HHR6A/6B and RAD18 proteins. 1277 93

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.
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PMID:Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. 1466 Jun 70

Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.
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PMID:PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. 1544 5


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