t(6;8), t(8;9) and t(8;13) translocations associated with stem cell myeloproliferative disorders have close or identical breakpoints in chromosome region 8p11-12

Chaffanet, Max; Popovici, Cornel; Leroux, Dominique; Jacrot, M.; Adélaı̈de, José; Dastugue, Nicole; Gregoire, Marie‐José; Hagemeijer, Anne; Lafage‐Pochitaloff, Marina; Birnbaum, Daniel; Pébusque, Marie‐Josèphe

doi:10.1038/sj.onc.1201601

Cited by 58 publications

(43 citation statements)

References 25 publications

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“…The translocations result in production of fusion proteins containing distinct Nterminal domains fused to the tyrosine kinase domain of FGFR1, which is constitutively active (MacDonald et al, 1995;Chaffanet et al, 1998;Popovici et al, 1999). KG-1 and KG-1a are AML-derived cell lines that express an FGFR1OP2-FGFR1 fusion protein.…”

Section: Discussionmentioning

confidence: 99%

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

et al. 2007

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Indirubin-3 0 -monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3 0 -monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3 0 -monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptormediated cell signaling. Indirubin-3 0 -monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3 0 -monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3 0 -monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3 0 -monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3 0 -monoxime that may have clinical implications.

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Section: Discussionmentioning

confidence: 99%

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

et al. 2007

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“…It is also called stem cell MPD or 8p12 (or 8p11) MPD because both lymphoid and myeloid lineages are affected following activation of the FGFR1 TK, which is encoded by a gene on the p11-12 region of chromosome 8. 4 Kinase attack at the centrosome The FGFR1 gene is rearranged 5 with several partners (designed X thereafter), among which CEP1, 6 FOP, 7 ZNF198 8,9 and BCR. 10,11 Some consequences of the translocation have been delineated.…”

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confidence: 99%

Myeloproliferative disorders: the centrosome connection

2005

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Some myeloproliferative disorders (MPD) result from a reciprocal translocation that involves the FGFR1 gene and a partner gene. The event creates a chimeric gene that encodes a fusion protein with constitutive FGFR1 tyrosine kinase activity. FGFR1-MPD is a rare disease, but its study may provide interesting clues on different processes such as cell signalling, oncogenesis and stem cell renewal. Some partners of FGFR1 are centrosomal proteins. The corresponding oncogenic fusion kinases are targeted to the centrosome. Constitutive phosphorylation at this site may perturbate centrosome function and the cell cycle. Direct attack at this small organelle may be an efficient way for oncogenes to alter regulation of signalling for proliferation and survival and get rid of checkpoints in cell cycle progression. The same effect might be triggered by other fusion kinases in other MPD and non-MPD malignancies.

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“…The chimaeric proteins with putative oncogenic properties contain potential oligomerization domains encoded by the 6q27 (FOP), 9q33 (CEP110) and 13q12 (FIM) genes fused to the tyrosine kinase domain of FGFR1. We have recently shown that the three fusion proteins are delocalized from their normal counterparts, display constitutive kinase activity triggered by dimerization mediated by the protein± protein interaction motifs of the FGFR1 protein partner and promote survival of pro-B Ba/F3 cells after IL-3 withdrawal (Ollendorff et al, 1999;Guasch et al, 2000). These accumulating data suggest that a common mechanism may sustain the oncogenic activity of the rearranged kinase.…”

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confidence: 96%

“…This MPD has been already associated with four reciprocal translocations t(6;8)(q27;p12), t(8;9)(p12;q33), t(8;13)(p12;q12) and t(8;17)(p12;q25). Three FGFR1 partner genes have been cloned, FOP at 6q27 (Popovici et al, 1999), CEP110 at 9q33 (Guasch et al, 2000) and FIM/ZNF198 at 13q12 Xiao et al, 1998). The 17q25 gene has not been identified to date (Sohal et al, 1999).…”

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confidence: 99%

The 8p12 myeloproliferative disorder. t(8;19)(p12;q13.3): a novel translocation involving the FGFR1 gene

Mugneret¹,

Chaffanet

Maynadié³

et al. 2000

Br J Haematol

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Summary. 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.Keywords: myeloproliferative disorder, translocation, FGFR1 gene, chromosome 8, chromosome 19.The FGFR1 gene encodes one of the four tyrosine kinase receptors for members of the fibroblast growth factor family and its disruption is the hallmark of a stem cell myeloproliferative disorder (MPD) linked to the 8p12 chromosomal region . This MPD has been already associated with four reciprocal translocations t(6;8)(q27;p12), t(8;9)(p12;q33), t(8;13)(p12;q12) and t(8;17)(p12;q25). Three FGFR1 partner genes have been cloned, FOP at 6q27 (Popovici et al, 1999), CEP110 at 9q33 (Guasch et al, 2000) and FIM/ZNF198 at 13q12 Xiao et al, 1998). The 17q25 gene has not been identified to date (Sohal et al, 1999). In all cases analysed to date, the FGFR1 breakpoints are tightly clustered in the 1´2 Kb intron 8 or near the exon 8/intron 8 junction. The chimaeric proteins with putative oncogenic properties contain potential oligomerization domains encoded by the 6q27 (FOP), 9q33 (CEP110) and 13q12 (FIM) genes fused to the tyrosine kinase domain of FGFR1. We have recently shown that the three fusion proteins are delocalized from their normal counterparts, display constitutive kinase activity triggered by dimerization mediated by the protein± protein interaction motifs of the FGFR1 protein partner and promote survival of pro-B Ba/F3 cells after IL-3 withdrawal (Ollendorff et al, 1999;Guasch et al, 2000). These accumulating data suggest that a common mechanism may sustain the oncogenic activity of the rearranged kinase.A 70-year-old man presented to the Dijon Hospital with a dermatological and acute renal disease paraneoplastic syndrome. Haemoglobin was 17 g/dl and the leucocyte count was 3´9 Â 10 9 /l, with 5% myelocytes and 7% blast cells. Platelet count was 140 Â 10 9 /l. The bone marrow aspirate showed 37% of peroxidase-negative blast cells, 25% of erythroblasts with dyserythropoiesis, abnormal megakaryocytes and 5% of eosinophiles (Fig 1A and B respectively). Immunophenotype was studied on fresh bone marrow mononuclear cells by flow cytometry. Blast cells were CD45 low and displayed cytoplasmic CD13 and myeloperoxidase. All lymphoid and other myeloid markers were negative. A diagnosis of acute myeloid leukaemia (AML) M0 probably secondary to a myeloproliferative disorder was made. The patient was treated with rubidazone/aracytine for 6 months and died 15 months later from increased renal disease. Cytogenetic study of the bone marrow revealed the karyotype abnormality t(8;19)(p12;q13.3) associated with loss of the Y chromosome in 14 out of 15 metaphases.The 8p12 MPD is characterized by common clinicopathological features: B-or T-cell lymphoblastic leukaemia/ lym...

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t(6;8), t(8;9) and t(8;13) translocations associated with stem cell myeloproliferative disorders have close or identical breakpoints in chromosome region 8p11-12

Cited by 58 publications

References 25 publications

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Myeloproliferative disorders: the centrosome connection

The 8p12 myeloproliferative disorder. t(8;19)(p12;q13.3): a novel translocation involving the FGFR1 gene

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