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Mariejosephe Pebusque - One of the best experts on this subject based on the ideXlab platform.
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long term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell Myeloproliferative Disorder associated with t 8 13 p12 q12
British Journal of Haematology, 2003Co-Authors: Florence Suzan, Geraldine Guasch, Christine Terre, Isabel Garcia, Jeannoel Bastie, Odile Maarek, Patricia Ribaud, Eliane Gluckman, Marietherese Daniel, Mariejosephe PebusqueAbstract:Summary. A rare atypical Myeloproliferative Disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11–p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this Disorder.
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endogenous retroviral sequence is fused to fgfr1 kinase in the 8p12 stem cell Myeloproliferative Disorder with t 8 19 p12 q13 3
Blood, 2003Co-Authors: Geraldine Guasch, Francine Mugneret, Max Chaffanet, Daniel Birnbaum, Cornel Popovici, Pierre Pontarotti, Mariejosephe PebusqueAbstract:FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell Myeloproliferative Disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33, FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5' sequences from HERV-K fused in frame to 3' FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts, HERV-K/FGFR1.
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8p12 stem cell Myeloproliferative Disorder the fop fibroblast growth factor receptor 1 fusion protein of the t 6 8 translocation induces cell survival mediated by mitogen activated protein kinase and phosphatidylinositol 3 kinase akt mtor pathways
Molecular and Cellular Biology, 2001Co-Authors: Geraldine Guasch, Daniel Birnbaum, Vincent Ollendorff, Jeanpaul Borg, Mariejosephe PebusqueAbstract:The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell Myeloproliferative Disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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the 8p12 Myeloproliferative Disorder t 8 19 p12 q13 3 a novel translocation involving the fgfr1 gene
British Journal of Haematology, 2000Co-Authors: Francine Mugneret, Max Chaffanet, Marc Maynadie, Geraldine Guasch, Bernardine Favre, Olivier Casasnovas, Daniel Birnbaum, Mariejosephe PebusqueAbstract:Translocations affecting the chromosomal locus 8p12 are hallmarks of an atypical stem cell Myeloproliferative Disorder. These events disrupt the fibroblast growth factor receptor 1 (FGFR1) gene and fuse the FGFR1 C-terminus catalytic domain with unrelated proteins. Here, we report on the characterization of the 19q13.3 locus as the fifth FGFR1 chromosomal partner.
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fgfr1 is fused to the centrosome associated proteincep110 in the 8p12 stem cell Myeloproliferative Disorder with t 8 9 p12 q33
Blood, 2000Co-Authors: Geraldine Guasch, Daniel Birnbaum, Cornel Popovici, Gary J Mack, Nicole Dastugue, Jerome B Rattner, Mariejosephe PebusqueAbstract:The hallmark of the 8p12 stem cell Myeloproliferative Disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion between FGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm.
Geraldine Guasch - One of the best experts on this subject based on the ideXlab platform.
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long term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell Myeloproliferative Disorder associated with t 8 13 p12 q12
British Journal of Haematology, 2003Co-Authors: Florence Suzan, Geraldine Guasch, Christine Terre, Isabel Garcia, Jeannoel Bastie, Odile Maarek, Patricia Ribaud, Eliane Gluckman, Marietherese Daniel, Mariejosephe PebusqueAbstract:Summary. A rare atypical Myeloproliferative Disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11–p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this Disorder.
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endogenous retroviral sequence is fused to fgfr1 kinase in the 8p12 stem cell Myeloproliferative Disorder with t 8 19 p12 q13 3
Blood, 2003Co-Authors: Geraldine Guasch, Francine Mugneret, Max Chaffanet, Daniel Birnbaum, Cornel Popovici, Pierre Pontarotti, Mariejosephe PebusqueAbstract:FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell Myeloproliferative Disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33, FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5' sequences from HERV-K fused in frame to 3' FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts, HERV-K/FGFR1.
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8p12 stem cell Myeloproliferative Disorder the fop fibroblast growth factor receptor 1 fusion protein of the t 6 8 translocation induces cell survival mediated by mitogen activated protein kinase and phosphatidylinositol 3 kinase akt mtor pathways
Molecular and Cellular Biology, 2001Co-Authors: Geraldine Guasch, Daniel Birnbaum, Vincent Ollendorff, Jeanpaul Borg, Mariejosephe PebusqueAbstract:The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell Myeloproliferative Disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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the 8p12 Myeloproliferative Disorder t 8 19 p12 q13 3 a novel translocation involving the fgfr1 gene
British Journal of Haematology, 2000Co-Authors: Francine Mugneret, Max Chaffanet, Marc Maynadie, Geraldine Guasch, Bernardine Favre, Olivier Casasnovas, Daniel Birnbaum, Mariejosephe PebusqueAbstract:Translocations affecting the chromosomal locus 8p12 are hallmarks of an atypical stem cell Myeloproliferative Disorder. These events disrupt the fibroblast growth factor receptor 1 (FGFR1) gene and fuse the FGFR1 C-terminus catalytic domain with unrelated proteins. Here, we report on the characterization of the 19q13.3 locus as the fifth FGFR1 chromosomal partner.
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fgfr1 is fused to the centrosome associated proteincep110 in the 8p12 stem cell Myeloproliferative Disorder with t 8 9 p12 q33
Blood, 2000Co-Authors: Geraldine Guasch, Daniel Birnbaum, Cornel Popovici, Gary J Mack, Nicole Dastugue, Jerome B Rattner, Mariejosephe PebusqueAbstract:The hallmark of the 8p12 stem cell Myeloproliferative Disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion between FGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm.
Daniel Birnbaum - One of the best experts on this subject based on the ideXlab platform.
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endogenous retroviral sequence is fused to fgfr1 kinase in the 8p12 stem cell Myeloproliferative Disorder with t 8 19 p12 q13 3
Blood, 2003Co-Authors: Geraldine Guasch, Francine Mugneret, Max Chaffanet, Daniel Birnbaum, Cornel Popovici, Pierre Pontarotti, Mariejosephe PebusqueAbstract:FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell Myeloproliferative Disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33, FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5' sequences from HERV-K fused in frame to 3' FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts, HERV-K/FGFR1.
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8p12 stem cell Myeloproliferative Disorder the fop fibroblast growth factor receptor 1 fusion protein of the t 6 8 translocation induces cell survival mediated by mitogen activated protein kinase and phosphatidylinositol 3 kinase akt mtor pathways
Molecular and Cellular Biology, 2001Co-Authors: Geraldine Guasch, Daniel Birnbaum, Vincent Ollendorff, Jeanpaul Borg, Mariejosephe PebusqueAbstract:The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell Myeloproliferative Disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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the 8p12 Myeloproliferative Disorder t 8 19 p12 q13 3 a novel translocation involving the fgfr1 gene
British Journal of Haematology, 2000Co-Authors: Francine Mugneret, Max Chaffanet, Marc Maynadie, Geraldine Guasch, Bernardine Favre, Olivier Casasnovas, Daniel Birnbaum, Mariejosephe PebusqueAbstract:Translocations affecting the chromosomal locus 8p12 are hallmarks of an atypical stem cell Myeloproliferative Disorder. These events disrupt the fibroblast growth factor receptor 1 (FGFR1) gene and fuse the FGFR1 C-terminus catalytic domain with unrelated proteins. Here, we report on the characterization of the 19q13.3 locus as the fifth FGFR1 chromosomal partner.
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fgfr1 is fused to the centrosome associated proteincep110 in the 8p12 stem cell Myeloproliferative Disorder with t 8 9 p12 q33
Blood, 2000Co-Authors: Geraldine Guasch, Daniel Birnbaum, Cornel Popovici, Gary J Mack, Nicole Dastugue, Jerome B Rattner, Mariejosephe PebusqueAbstract:The hallmark of the 8p12 stem cell Myeloproliferative Disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion between FGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm.
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characterization of fim fgfr1 the fusion product of the Myeloproliferative Disorder associated t 8 13 translocation
Journal of Biological Chemistry, 1999Co-Authors: Vincent Ollendorff, Geraldine Guasch, Daniel Birnbaum, Daniel Isnardon, Remy Galindo, Mariejosephe PebusqueAbstract:Abstract The t(8;13) translocation found in a rare type of stem cell Myeloproliferative Disorder generates a constitutively activated tyrosine kinase containing N-terminal sequence encoded by theFIM gene linked to the FGFR1 kinase domain. Here we have further characterized FIM and FIM-FGFR1 proteins. Firstly, we have studied their respective subcellular localization. We show that FIM has nuclear and nucleolar localization, whereas FIM-FGFR1 is mainly cytoplasmic. Within the nucleolus, FIM colocalizes with the upstream binding factor in interphasic cells, indicating that FIM may be involved in the regulation of rRNA transcription. We demonstrate that the targetting of FIM to the nucleus depends upon its C-terminal region, which is absent in the cytoplasmic FIM-FGFR1 protein. Secondly, we demonstrate that FIM-FGFR1 has constitutive dimerization capability mediated by the FIM N-terminal sequences. Finally, we show that FIM-FGFR1 promotes survival of pro-B Ba/F3 cells after interleukin-3 withdrawal, whereas ligand-activated FGFR1 induced not only cell survival but also interleukin-3 independence. Taken together, these results indicate that FIM-FGFR1 is activated by dimerization as a cytoplasmic kinase and suggest that FIM-FGFR1 partially signals through the FGFR1 pathways.
Cornel Popovici - One of the best experts on this subject based on the ideXlab platform.
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dual lympho Myeloproliferative Disorder in a patient with t 8 22 with bcr fgfr1 gene fusion
International Journal of Oncology, 2005Co-Authors: Anne Murati, Christine Arnoulet, Marina Lafagepochitaloff, Jose Adelaide, Martine Derre, Borhane Slama, Benedicte Delaval, Cornel Popovici, Luc Xerri, Marie Joelle MozziconacciAbstract:The case of a patient presenting with a Myeloproliferative Disorder (MPD) characterized by a t(8;22) (p12;q11) translocation was investigated. The rearrangement resulted in the production of BCR-FGFR1 and FGFR1-BCR chimeric transcripts after in-frame fusions of BCR exon 4 with FGFR1 exon 9 and FGFR1 exon 8 with BCR exon 5, respectively. The four previously reported patients with such translocation presented with an atypical chronic myeloid leukemia (CML) without Philadelphia chromosome. In addition to a myeloproliferation, the patient had a B cell proliferation. The phenotypic characterization of the lymphoid cells in the bone marrow showed a continuum of maturation from blast B cells to polyclonal lymphocytes. In the blood, B cells showed a complete polyclonal maturation. The BCR-FGFR1 gene fusion was detected by dual-color fluorescence in situ hybridization in both CD19 - and CD19 + populations. In contrast to the other FGFR1-MPDs that show myeloid and T cell proliferation, we propose that this t(8;22) MPD is a myeloid and B cell disease, and potentially a novel type of hematological disease. Although the FGFR1-MPD is rare, its study provides interesting clues to the understanding of hematopoietic stem cell biology and oncogene activation.
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endogenous retroviral sequence is fused to fgfr1 kinase in the 8p12 stem cell Myeloproliferative Disorder with t 8 19 p12 q13 3
Blood, 2003Co-Authors: Geraldine Guasch, Francine Mugneret, Max Chaffanet, Daniel Birnbaum, Cornel Popovici, Pierre Pontarotti, Mariejosephe PebusqueAbstract:FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell Myeloproliferative Disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33, FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5' sequences from HERV-K fused in frame to 3' FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts, HERV-K/FGFR1.
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fgfr1 is fused to the centrosome associated proteincep110 in the 8p12 stem cell Myeloproliferative Disorder with t 8 9 p12 q33
Blood, 2000Co-Authors: Geraldine Guasch, Daniel Birnbaum, Cornel Popovici, Gary J Mack, Nicole Dastugue, Jerome B Rattner, Mariejosephe PebusqueAbstract:The hallmark of the 8p12 stem cell Myeloproliferative Disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion between FGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm.
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the t 6 8 q27 p11 translocation in a stem cell Myeloproliferative Disorder fuses a novel gene fop to fibroblast growth factor receptor 1
Blood, 1999Co-Authors: Cornel Popovici, Daniel Birnbaum, Marina Lafagepochitaloff, Bin Zhang, Mariejose Gregoire, Philippe Jonveaux, Mariejosephe PebusqueAbstract: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 ( F GFR1 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 -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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fibroblast growth factor receptor 1 is fused to fim in stem cell Myeloproliferative Disorder with t 8 13 p12 q12
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Cornel Popovici, Max Chaffanet, Geraldine Guasch, Daniel Birnbaum, Vincent Ollendorff, Jose Adelaide, Michele Jacrot, Dominique Leroux, Mariejosephe PebusqueAbstract:Chromosome 8p11–12 is the site of a recurrent breakpoint in a Myeloproliferative Disorder that involves lymphoid (T- or B-cell), myeloid hyperplasia and eosinophilia, and evolves toward acute leukemia. This multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell. In this Disorder, the 8p11–12 region is associated with three different partners 6q27, 9q33, and 13q12. We describe here the molecular characterization of the t(8;13) translocation that involves the FGFR1 gene from 8p12, encoding a tyrosine kinase receptor for members of the fibroblast growth factor family, and a gene from 13q12, tentatively named FIM (Fused In Myeloproliferative Disorders). FIM is related to DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1; this defines a gene family involved in different human pathologies. The two reciprocal fusion transcripts, FIM/FGFR1 and FGFR1/FIM are expressed in the malignant cells. The FIM/FGFR1 fusion protein contains the FIM putative zinc finger motifs and the catalytic domain of FGFR1. We show that it has a constitutive tyrosine kinase activity.
John K Cowell - One of the best experts on this subject based on the ideXlab platform.
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genetic fingerprinting of the development and progression of t cell lymphoma in a murine model of atypical Myeloproliferative Disorder initiated by the znf198 fibroblast growth factor receptor 1 chimeric tyrosine kinase
Blood, 2009Co-Authors: Xiurong Li, John K CowellAbstract:A mouse model of human ZNF198–fibroblast growth factor receptor-1 (FGFR1) stem cell leukemia lymphoma has been developed to investigate mechanisms of oncogenesis and progression. Using array-based comparative genomic hybridization, we followed disease progression after serial transplantation of ZNF198-FGFR1–transformed stem cells that give rise to a distinct Myeloproliferative Disorder and T-lymphoblastic leukemia. A consistent, frequently homozygous, chr14:53880459-55011545 deletion, containing the T-cell receptor α and δ genes, was identified in the bone marrow, spleen, and lymph nodes in all cases. The absence of cell-surface T-cell receptor α in tumor cells precludes CD3 recruitment, resulting in loss of a functional T-cell receptor complex, supporting the idea that prevention of maturation of CD4+/CD8+ double-positive immature T cells is important in ZNF198-FGFR1 disease development. Up-regulation of the B-cell line 2, interleukin 7 receptor α and interleuking 2 receptor α prosurvival genes in these undifferentiated tumor precursor cells suggests one mechanism that allows them to escape apoptosis in the thymus. Thus, we have defined an important event in the process of ZNF198-FGFR1–induced T-cell leukemia.
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the t 8 13 atypical Myeloproliferative Disorder further analysis of the znf198 gene and lack of evidence for multiple genes disrupted on chromosome 13
Blood, 1998Co-Authors: Ivan H Still, John K CowellAbstract:To The Editor: An atypical Myeloproliferative Disorder has been described that is associated with T-cell leukemia/lymphoma and peripheral blood eosinophilia.[1][1] All these cases are associated with a translocation between 8p11 and 13q11-12 or two rare variant translocations involving 8p11 and
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molecular characterization of the t 8 13 p11 q12 translocation associated with an atypical Myeloproliferative Disorder evidence for three discrete loci involved in myeloid leukemias on 8p11
Blood, 1997Co-Authors: Ivan H Still, Olga Chernova, David D Hurd, Richard Stone, John K CowellAbstract:A reciprocal chromosome translocation between 13q12 and 8p11 is the consistent cytogenetic abnormality seen in a nonspecific Myeloproliferative Disorder that is associated with T-cell leukemia/lymphoma and peripheral blood eosinophilia. Detailed molecular analyses of the translocation breakpoints associated with this rearrangement have not been reported to date. We have now generated somatic cell hybrids from a newly described patient with this specific structural rearrangement and analyzed the breakpoints on the derivative chromosomes. We have shown that the breakpoint on chromosome 13 lies within a 300- to 500-kb region defined by the KIAA177 gene and D13S1123 marker. In addition, we have identified a 1.2-Mb YAC, 959A4, that crosses the translocation breakpoint on the short arm of chromosome 8 in this patient. The location of this breakpoint in 8p11 is distinct from the t(8; 16) and t(8; 22) translocations associated with M4/M5 myeloid leukemias, and suggests that three distinct loci located within 8p11 are involved in the pathogenesis of myeloid neoplasias.
