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.
Although several issues remain to be clarified,1 molecular mechanisms of oncogenesis leading to malignant haemopathies have been characterised.2 They frequently involve reciprocal chromosomal translocations, which schematically generate two classes of fusion genes. The first class, found in acute myeloid leukaemias (AML), involves genes encoding transcription regulators; the fusion genes promote cell survival and impair differentiation. The second class, found in myeloproliferative disorders (MPD), involves tyrosine kinase (TK) genes; the resulting chimeric protein products are constitutively activated TK that induce cell survival and proliferation. The BCR-ABL fusion was the first fusion TK to be characterised. It is specific of chronic myelogenous leukaemia (CML), a frequent typical MPD, and results from a t(9;22) translocation.
MPDs are clonal haematological diseases that affect progenitor cells; cells from the myeloid lineage, and sometimes from other lineages as well,3 proliferate continuously but, in contrast to AML, undergo maturation. MPDs comprise typical MPDs (CML, polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis) and various other types of disorders. We have represented in Figure 1 various fusions issued from chromosomal rearrangements in MPDs. The FGFR1-MPD is a rare and aggressive atypical MPD. 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 rearranged5 with several partners (designed X thereafter), among which CEP1,6 FOP,7 ZNF1988, 9 and BCR.10, 11 Some consequences of the translocation have been delineated. X-FGFR1 proteins contain both a constitutively activated FGFR1 TK and partner dimerisation motifs or domains.12, 13, 14 They promote cell survival through signalling pathways involving, among others, phospholipase C γ (PLCγ), phosphoinositol 3 kinase (PI3K), AKT and STAT proteins.12, 15, 16 FGFR1-MDPs have been reproduced in mouse bone marrow transplantation models.17, 18, 19
Recent results have shown that at least two of the FGFR1 partners, CEP1 and FOP, are bona fide centrosomal proteins. The centrosome, also called microtubule-organising centre (MTOC), is a small cellular organelle essential for microtubule organisation and nucleation. CEP1 is a well-characterised centrosomal protein20 with a coiled-coil structure and leucine zipper motifs (Figure 2). It has no obvious orthologue in nonvertebrates. A comprehensive proteomic analysis of the centrosome has recently included FOP in the list of centrosomal proteins.21 In agreement, our immunofluorescence experiments have revealed the presence of FOP at the centrosome.22 FOP has a potential homologue in Arabdiopsis thaliana named tonneau. FOP, tonneau and various other eukaryotic proteins share a sequence motif of ca. 30-amino-acid residues named LisH (lissencephaly homology domain). Human LisH-containing proteins LIS1/PAFAH1B1, TCOF1, OFD1 and TBL1X are mutated in Miller–Dieker lissencephaly, Treacher–Collins syndrome, orofacial-digital syndrome 1 and contiguous syndrome ocular albinism with late-onset sensorineural deafness, respectively.23 LIS1 protein is localised predominantly at the centrosome.24 LisH is a thermodynamically very stable dimerisation domain25 that contributes to the regulation of microtubule dynamics, either by mediating dimerisation or by binding cytoplasmic dynein heavy chain or microtubules directly.
The centrosomal localisation of some FGFR1 partners led us to hypothesise that the corresponding X-FGFR1 fusion kinases may be addressed to the centrosome. The motif that targets CEP1 to the centrosome is retained in the chimeric CEP1-FGFR1 protein and this fusion product has therefore the potential to be targeted to the centrosome.6 Indeed, our immunofluorescence experiments localised FOP-FGFR1 and CEP1-FGFR1 at the centrosome in transfected Ba/F3 cells.22 FOP-FGFR1 also localises at the centrosome in MPD mouse cells.22 Thus, the FGFR1 partner protein does not only provide dimerisation domain but also ensures specific addressing of the oncogenic kinase to a restricted site of action.
Do malignant haemopathies show a general way once more?
How many MPDs are centrosomal diseases?
A recent analysis of an FGFR1-MPD showed that a t(8;17) translocation resulted in an MYO18A-FGFR1 chimeric protein. 26 MYO18B, encoded by a paralogue of MYO18A, is found at the centrosome.21 Moreover, we have found that MYO18A interacts with CEP1 (L Daviet and D Birnbaum, unpublished). It is thus likely that MYO18A-FGFR1, like FOP-FGFR1 and CEP1-FGFR1, targets the centrosome. However, centrosomal localisation may not be necessary to trigger the disease. ZNF198-FGFR1 and BCR-FGFR1,10, 12, 14 the two other well-characterised fusion kinases of FGFR1-MPDs, have been found predominantly in the cytoplasm of cells using expressed GFP fusions. BCR-FGFR1 is not directly targeted to the centrosome even if signalling could relay at this organelle.22 The recently discovered TIF1-FGFR1 fusion27 is not suggestive of a centrosome localisation.
Conversely, FOP-FGFR1 and CEP1-FGFR1 might not be the only MPD kinases to target the centrosome. In addition to FGFR1, several other TKs (Figure 1) are involved in MPDs and other partners of TKs have been described. These partners are ninein (NIN) in t(5;14) with NIN-PDGFRB fusion,28 TRIP11/CEV14/GMAP210 in t(5;14) with CEV14-PDGFRB fusion,29 H4 in t(5;10) with H4-PDGFRB fusion,30 rabaptin 5 in t(5;17) with RABEP1-PDGFRB fusion,31 HCMOGT1 in t(5;17) with HCMOGT1-PDGFRB fusion,32 PDE4DIP/myomegalin in t(1;5) with PDE4DIP-PDGFRB fusion,33 an uncharacterised protein in t(5;14),34 TP53BP1 in t(5;15) with TP53BP1-PDGFRB fusion35 and FIP1L1 in del(4q) with FIP1L1-PDGFRA fusion.36, 37
NIN is a bona fide centrosomal protein. Other PDGFR partners may also be localised at the centrosome (Figure 2). The coiled-coil TRIP11 protein associates with the minus end of microtubules, which accumulate at the centrosome.38 Myomegalin has coiled coils such as that found in microtubule-associated proteins and a leucine zipper identical to that of Drosophila centrosomin.39 Both TRIP11 and myomegalin are proteins of the Golgi/centrosome region. Myomegalin was included in the list of centrosomal proteins detected by mass spectrometry.21 H4/CCDC6 is a coiled-coil protein that is also fused to the RET TK in thyroid carcinomas.40 Rabaptin 5 and HCMOGT1 have also coiled-coil domains; Rabaptin 5 is found in the endosomes. TP53BP1 controls the G2/M checkpoint.41 FIP1L1 belongs to a polyadenylation complex. Recently, a new fusion involving JAK2 kinase and centrosomal protein PCM1 has been described in MPDs.42, 43, 44 Two other proteins very frequently involved with TKs in MPDs are BCR and ETV6/TEL. Studies on the subcellular localisation of BCR and ETV6 have not suggested centrosomal localisation.
Finally, in addition to fusion proteins, some cytoplasmic TKs might directly target the centrosome in the course of their normal functions.45, 46, 47 This addressing may be conserved in an oncogenic fusion.48 One of these kinases, JAK2, is constitutively activated by point mutations in MPD.49, 50, 51, 52 Fused or mutated, these TKs might affect the cell cycle through, among other possibilities, an altered centrosomal function.
A model for leukaemogenesis, perhaps more
We have proposed that some TK alterations target the centrosome and lead to MPD. Translocation-activated TKs are found in other types of cancer, in particular lymphomas and sarcomas.53 The ALK TK receptor is involved in both anaplastic lymphomas and inflammatory myofibroblastic tumours. Centrosome abnormalities are observed in ALK-positive lymphomas.54, 55 The preferred partner of ALK is nucleophosmin (NPM1). A recent study has shown that nucleophosmin is mutated in AMLs.56 At some periods of the cell cycle, nucleophosmin transits through the centrosome. Thus, NPM1-ALK fusion kinase and mutated NPM1 may perturbate processes associated with centrosome function. Another protein involved in oncogenic fusion is PML. PML has also been found at the centrosome recently.57 Centrosome alteration might also occur in epithelial cancers, in which some examples of translocations leading to chimeric TK activation have been described.40, 58, 59
However, all fusion proteins will not target the centrosome. Still, some of the oncogenic kinases that are not addressed to the centrosome may target subcellular sites that are involved in the control of cell division in coordination with this organelle, for example, the Golgi apparatus or the nucleolus, or may use some relays at the centrosome, as suggested for BCR-FGFR1.22 The centrosome is linked either directly or via microtubule tracks to many other subcellular areas, and signalling may transit through the centrosome via vesicular transport. Oncogenes may thus target the centrosome from the distance.
Numerical and functional alterations of the centrosome in cancer
Centrosome alterations are frequent in various types of cancer, including haematological diseases.60 In normal conditions, the centrosome undergoes duplication precisely once per cell division during the G1/S transition. Centrosome amplification, which can result from disruption, cell fusion, overduplication, de novo formation or aborted cell division,61, 62 has been described as a major cause of aneuploidy.63 In AMLs, both structural and numerical chromosome aberrations are frequent and provide diagnostic and prognostic information.64 Structural and numerical alterations of centrosomes are also common in non-Hodgkin's lymphomas and may contribute to the chromosomal instability typically seen in these diseases.65 It is worth noting here that Hodgkin's lymphomas frequently show amplification of the JAK2 gene region.66 Structural and numerical centrosomal abnormalities have also recently been described in CML; they correlate with the stage of the disease and chromosomal instability.67
MPD cells are not particularly aneuploid at the chronic phase. The translocation that generates the chimeric TK gene is often the only karyotypic abnormality. Moreover, cells overexpressing an X-FGFR1 fusion kinase in experimental systems are not aneuploid and do not show amplification of the centrosomes. If X-FGFR1 proteins exert their oncogenic effect at the centrosome, it does not result in abnormal centrosome number and in aneuploidy. Another mechanism affecting centrosome function must be involved.
Thus, in human haematological diseases, centrosomes may not only show amplification leading to chromosomal instability and aneuploidy but also alteration of function without alteration in number. This might be true for other cancers as well.
What could be the effects of a centrosomal oncogenic kinase on centrosome function?
The presence of a constitutively active X-FGFR1 kinase at the centrosome may affect several processes associated with the function of this organelle. More than just an MTOC, the centrosome is important for the regulation of cell cycle progression.68, 69, 70 It also influences cell shape, polarity and motility and is linked to DNA repair.71, 72 Accordingly, many proteins involved in these processes are found at the centrosome, including cyclins, BRCA1, P53, and various kinases, phosphatases, signalling substrates and cell cycle regulators.21, 73 Our recent results indicate that X-FGFR1 at the centrosome deregulates G1/S events, and particularly the restriction point from G1-phase to S-phase, when centrosome duplication occurs.22 Abnormal activation of X-FGFR1 at the centrosome may affect the regulation of various molecular complexes. It may activate a proliferation signal at the centrosome, relieve a brake on the cell cycle, and simultaneously perturbate apoptosis in the targeted stem cell, which would subsequently survive and divide continuously. Directly targeting a constitutively active kinase to the centrosome could activate and/or recruit key regulators of cell cycle such as cyclins. Several potential processes can be affected such as regulation of transcription, cell cycle regulator recruitment or stabilisation, and control of mRNA translation. It can also directly affect centrosome structure (but not number),60 and therefore function, by interacting, stabilising, recruiting or activating known core centrosomal proteins (eg CAP350, centrin) or cell cycle regulators such as RB1, cyclins, CDKs or CDK inhibitors.
Centrosome duplication is tightly coordinated with chromosome duplication and cell cycle entry. To allow constitutive entry in S-phase, the ectopic fusion TK may directly activate centrosome duplication, which is initiated at the G1/S transition of the cell cycle and completed before mitosis. This could occur by phosphorylation and direct activation of downstream kinases (CDK2, PLK, JNK, PI3K) and/or other signalling proteins important for centrosome duplication.72 PI3K for example, a known X-FGFR1 downstream target, is involved in centrosome duplication.72 Cyclins D, and cyclin E/CDK2 complex, which is involved in both the coordination of DNA replication and centrosome duplication, would constitute good targets for X-FGFR1 kinase. Cyclin E centrosomal localisation is important to accelerate S-phase entry.74
Finally, FGFR1 fusion partners, because they are centrosomal proteins, may not only provide neutral dimerisation domains and addressing motifs but could also participate actively to the oncogenic process. A bidirectional oncogenic effect could thus be created, one through constitutive TK activation, and the other one through disruption of partner function. However, there is no evidence in support of this hypothesis.
The centrosome: an integrating platform for normal cell signalling perverted in diseases?
Studies of nature accidents can prove very informative. Viral oncogenes led scientists to suspect the existence of normal cellular counterparts. Ectopic cellular oncogenes may give us clues about normal cell control. An ectopically activated kinase cannot create an entirely new system to function but, like viruses, must prey upon existing networks. Receptors for external regulatory peptides transmit the signals towards the interior of the cell as phosphorylation cues. The signal journey ends in the nucleus, inducing the transcription machinery to give the appropriate response. The passage of signals through the cytoplasm is considered as a neutral transition without much interest, usually sketched as coarse arrays of arrows. We propose in contrast that signals from the cell surface transit through the centrosome. We believe that not only this small organelle is associated with cell division through the organisation of microtubules but that it also deals directly with the signals associated with this process. In other words, the centrosome might integrate various signalling pathways aimed at triggering cell division. Many signalling molecules, such as PI3K, PLCγ, MAP kinases and AKT, are found at the centrosome.21 The PI3K-AKT pathway is particularly interesting in this context. This pathway, by means of transcriptional and post-transcriptional events,75 is associated with cell survival and cell proliferation, which are the two cell processes predominantly affected in MPD. It is directly involved in the control of the cell cycle in regulating G1 cyclins D1 and E.76 Degradation of cyclin D1 upon GSK3β phosphorylation is inhibited by the AKT pathway. Pools of both AKT and GSK3β are found at the centrosome.77 Similarly, the FGFR1 signalling pathway upregulates D cyclins.78 NIN, a fusion partner of PDGFRB in MPD, interacts with GSK3 kinase.
Owing to its location in the cytoplasm, at the crossroads of microtubules, close to the nucleus and the proteasome, and connected to the Golgi apparatus, the centrosome as an ‘integrating centre’ can be an easy prey for pathogens in various diseases. Directly attacking this organelle could be a convenient way for oncogenes, mutated regulators (eg NPM), fusion kinases (eg FOP-FGFR1, NIN-PDGFRB, PCM1-JAK2) and viral proteins79 to perturbate signalling pathways normally leading to regulated cell survival, cell proliferation and cell division, especially if this occurs in stem cells. It may one day become interesting to design drugs that target proteins specifically at the centrosome.
The centrosome: a trigger for stem cells to enter the cell cycle?
MPDs are diseases of haematopoietic progenitors. Characterisation of the mechanisms that induce sustained cycling of these cells is important for our understanding of stem cell biology. The centrosome may serve as a trigger for the stem cell to enter the cell cycle. Here again, the PI3K-AKT pathway could play an important role.80 Targeting a constitutively activated TK directly on key controls of both haematopoietic stem cell proliferation and survival may be the mechanism that governs MPD pathogenesis (Figure 3). The centrosomal fusion kinase, which deregulates and overcomes checkpoint arrest allowing constitutive G1/S progression, may affect the process of asymmetric division. We cannot exclude that centrosomal kinases also induce G0/G1 progression in stem cells, but it remains to be demonstrated.
MPDs and continuous proliferation: molecular understanding of precancerous lesions?
The study of FGFR1-MPD can perhaps teach us other general lessons. MPD is characterised by survival and proliferation. Survival is intrinsic to stem cell biology and, as we have proposed for FOP-FGFR1, proliferation is due to sustained G1/S transition and triggering of centrosome duplication. Apart from these characteristics, the MPD proliferating cell is quite normal and does not show extensive genome mutations and mitotic defects. One alteration (eg a mutation or translocation in the case of an MPD), leading to the perturbation of centrosome-associated processes, is sufficient to affect the G1/S transition and trigger proliferation. We believe these mechanisms will be found in other if not all cell proliferations associated with hyperplasia and precancerous states. In that sense, MPDs might also be considered, at the very beginning of the disease, as precancerous states. Secondary alterations, associated with other periods and checkpoints of the cell cycle, subsequently generate genome instability and aneuploidy, and trigger the full spectrum of malignant cell chaos.
Passegué E, Jamieson CH, Ailles LE, Weissman IL . Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA 2003; 100 (Suppl. 1): 11842–11849.
Gilliland DG . Molecular genetics of human leukemias: new insights into therapy. Semin Hematol 2002; 39: 6–11.
Murati A, Arnoulet C, Lafage-Pochitaloff M, Adélaïde J, Derré M, Slama B et al. Dual lympho-myeloproliferative disorder in a patient with t(8;22) with BCR-FGFR1 gene fusion. Int J Oncol 2005; 26: 1485–1492.
Cross NC, Reiter A . Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 2002; 16: 1207–1212.
Chaffanet M, Popovici C, Leroux D, Jacrot M, Adélaïde J, Dastugue N et al. 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. Oncogene 1998; 16: 945–949.
Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, Rattner JB et al. FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). Blood 2000; 95: 1788–1796.
Popovici C, Zhang B, Grégoire MJ, Jonveaux P, Lafage-Pochitlaoof M, Birnbaum D et al. 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 1999; 93: 1381–1389.
Popovici C, Adélaide J, Ollendorff V, Chaffanet M, Guasch G, Jacrot M et al. Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13). Proc Natl Acad Sci USA 1998; 95: 5712–5717.
Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES et al. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nat Genet 1998; 18: 84–87.
Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen SL et al. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 2001; 98: 3778–3783.
Fioretos T, Panagopoulos I, Lassen C, Swedin A, Billstrom R, Isaksson M et al. Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: the first fusion gene involving BCR but not ABL. Genes Chromosomes Cancer 2001; 32: 302–310.
Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, Pébusque MJ . Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation. J Biol Chem 1999; 274: 26922–26930.
Xiao S, McCarthy JG, Aster JC, Fletcher J . ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain. Blood 2000; 96: 699–704.
Baumann H, Kunapuli P, Tracy E, Cowell JK . The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 has signaling function comparable with interleukin-6 cytokine receptors. J Biol Chem 2003; 278: 16198–16208.
Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pébusque MJ . 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. Mol Cell Biol 2001; 21: 8129–8142.
Heath C, Cross NC . Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. J Biol Chem 2004; 279: 6666–6673.
Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M et al. PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA 2004; 101: 14479–14484.
Guasch G, Delaval B, Arnoulet C, Xie MJ, Xerri L, Sainty D et al. FOP-FGFR1 tyrosine kinase, the product of a t(6;8) translocation, induces a fatal myeloproliferative disease in mice. Blood 2004; 103: 309–312.
Roumiantsev S, Krause DS, Neumann CA, Dimitri CA, Asiedu F, Cross NC et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell 2004; 5: 287–298.
Ou YY, Mack GJ, Zhang M, Rattner JB . CEP110 and ninein are located in a specific domain of the centrosome associated with centrosome maturation. J Cell Sci 2002; 115: 1825–1835.
Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M . Proteomic characterization of the human centrosome by protein correlation profiling. Nature 2003; 426: 570–574.
Delaval B, Létard S, Lelièvre H, Chevrier V, Daviet L, Dubreuil P et al. oncogenic kinase of malignant hemopathy targets the centrosome. Cancer Res 2005; 65 (in press).
Emes RD, Ponting CP . A new sequence motif linking lissencephaly, Treacher–Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration. Hum Mol Genet 2001; 10: 2813–2820.
Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG . Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol 2004; 165: 709–721.
Kim MH, Cooper DR, Oleksy A, Devedjiev Y, Derewenda U, Reiner O et al. The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications. Structure (Cambridge) 2004; 12: 987–998.
Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Hochhaus A et al. The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia 2005; 19: 1005–1009.
Belloni E, Trubia M, Gasparini P, Mecucci C, Tapinassi C, Confalioneri S et al. 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosomes Cancer 2005; 42: 320–325.
Vizmanos JL, Novo FJ, Roman JP, Baxter EJ, Lahortiga I, Odero MD et al. NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder. Cancer Res 2004; 64: 2673–2676.
Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H . Fusion of the platelet-derived growth factor receptor β to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 1997; 90: 4271–4277.
Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF et al. Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res 2000; 60: 3592–3598.
Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger LA, Barrett AJ et al. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood 2001; 98: 2518–2525.
Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, Locatelli F et al. HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2). Cancer Res 2004; 64: 2649–2651.
Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA et al. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood 2003; 102: 4187–4190.
Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM et al. KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Leukemia 2005; 19: 27–30.
Grand FH, Burgstaller S, Kuhr T, Baxter EJ, Webersinke G, Thaler J et al. P53-binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res 2004; 64: 7216–7219.
Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutre SE et al. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004; 103: 2879–2891.
Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 2004; 18: 734–742.
Infante C, Ramos-Morales F, Fedriani C, Bornens M, Rios RM . GMAP-210, a cis-Golgi network-associated protein, is a minus end microtubule-binding protein. J Cell Biol 1999; 145: 83–98.
Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D et al. Myomegalin is a novel protein of the Golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J Biol Chem 2001; 276: 11189–11198.
Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA . RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol 2003; 195: 168–186.
Wang B, Matsuoka S, Carpenter PB, Elledge SJ . 53BP1, a mediator of the DNA damage checkpoint. Science 2002; 298: 1435–1438.
Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: 2662–2667.
Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B, Delsol G et al. The t(8;9)(p22;p24) translocation in atypical chronic myeloproliferative disorders yields a new PCM1-JAK2 fusion gene. Oncogene (in press).
Murati A, Gelsi-Boyer V, Adélaïde J, Perot C, Talmant P, Giraudier S et al. PCM1-JAK2 fusion in myeloproliferative disorders and acute erythtroid leukemia with t(8;9) translocation. Leukemia 2005, 21 July [E-pub ahead of print].
Faruki S, Geahlen RL, Asai DJ . Syk-dependent phosphorylation of microtubules in activated B-lymphocytes. J Cell Sci 2000; 113: 2557–2565.
Takahashi S, Inatome R, Hotta A, Qin Q, Hackenmiller R, Simon MC et al. Role for Fes/Fps tyrosine kinase in microtubule nucleation through is Fes/CIP4 homology domain. J Biol Chem 2003; 278: 49129–49133.
Steindler C, Li Z, Algarte M, Alcover A, Libri V, Ragimbeau J et al. Jamip1 (marlin-1) defines a family of proteins interacting with janus kinases and microtubules. J Biol Chem 2004; 279: 43168–43177.
Kuno Y, Abe A, Emi N, Iida M, Yokozawa T, Towatari M et al. Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 2001; 97: 1050–1055.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.
Tuveson DA, Fletcher JA . Signal transduction pathways in sarcoma as targets for therapeutic intervention. Curr Opin Oncol 2001; 13: 249–255.
Kutok JL, Aster JC . Molecular biology of anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma. J Clin Oncol 2002; 20: 3691–3702.
Ventura RA, Martin-Subero JI, Knippschild U, Gascoyne RD, Delsol G, Mason DY et al. Centrosome abnormalities in ALK-positive anaplastic large-cell lymphoma. Leukemia 2004; 18: 1910–1911.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.
Xu ZX, Zou WX, Lin P, Chang KS . A role for PML3 in centrosome duplication and genome stability. Mol Cell 2005; 17: 721–732.
Corvi R, Berger N, Balczon R, Romeo G . RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 2000; 19: 4236–4242.
Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk M, Mathers JA et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002; 2: 367–376.
Kramer A, Neben K, Ho AD . Centrosomal aberrations in hematological malignancies. Cell Biol Int 2005; 29: 376–384.
Nigg EA . Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2: 815–825.
Storchova Z, Pellman D . From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 2004; 5: 45–54.
Brinkley BR . Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol 2001; 11: 18–21.
Neben K, Tews B, Wrobel G, Hahn M, Kokocinski F, Giesecke C et al. Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes. Oncogene 2004; 23: 2379–2384.
Kramer A, Schweizer S, Neben K, Giesecke C, Kalla J, Katzenberger T et al. Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin's lymphoma. Leukemia 2003; 17: 2207–2213.
Joos S, Kupper M, Ohl S, von Bonin F, Mechtersheimer C, Bentz M et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res 2000; 60: 549–552.
Giehl M, Fabarius A, Frank O, Hochhaus A, Hafner M, Hehlmann R et al. Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability. Leukemia 2005; 19: 1192–1197.
Hinchcliffe EH, Miller FJ, Cham M, Khodjakov A, Sluder G . Requirement of a centrosomal activity for cell cycle progression through G1 into S phase. Science 2001; 291: 1547–1550.
Khodjakov A, Rieder CL . Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J Cell Biol 2001; 153: 237–242.
Rieder CL, Faruki S, Khodjakov A . The centrosome in vertebrates: more than a microtubule-organizing center. Trends Cell Biol 2001; 11: 413–419.
Griffin CS . Aneuploidy, centrosome activity and chromosome instability in cells deficient in homologous recombination repair. Mutat Res 2002; 504: 149–155.
Wang Q, Hirohashi Y, Furuuchi K, Zhao H, Liu Q, Zhang H et al. The centrosome in normal and transformed cells. DNA Cell Biol 2004; 23: 475–489.
D’Assoro AB, Lingle WL, Salisbury JL . Centrosome amplification and the development of cancer. Oncogene 2002; 21: 6146–6153.
Matsumoto Y, Maller JL . A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 2004; 306: 885–888.
Massague J . G1 cell-cycle control and cancer. Nature 2004; 432: 298–306.
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17: 590–603.
Wakefield JG, Stephens DJ, Tavare JM . A role for glycogen synthase kinase-3 in mitotic spindle dynamics and chromosome alignment. J Cell Sci 2003; 116: 637–646.
Koziczak M, Holbro T, Hynes NE . Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene 2004; 23: 3501–3508.
Münger K, Duensing S . Human papillomavirus infection and centrosome anomalies in cervical cancer. In: Nigg E (ed). Centrosomes in Development and Disease. New York: Wiley-VCH, 2004, pp 353–370.
Paling NR, Wheadon H, Bone HK, Welham MJ . Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. J Biol Chem 2004; 279: 48063–48070.
Work in our laboratory on MPD is supported by Inserm, Institut Paoli-Calmettes, Association Laurette Fugain and Ministries of Health and Research (Cancéropôle). BD has been successively supported by Ministry of Research, Ligue Nationale Contre le Cancer and Société Française d’Hématologie.
About this article
Cite this article
Delaval, B., Lelièvre, H. & Birnbaum, D. Myeloproliferative disorders: the centrosome connection. Leukemia 19, 1739–1744 (2005). https://doi.org/10.1038/sj.leu.2403926
- cell cycle
- myeloproliferative disorder
- tyrosine kinase
DLGAP1 directs megakaryocytic growth and differentiation in an MPL dependent manner in hematopoietic cells
Biomarker Research (2019)
Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies
Critical Reviews in Oncology/Hematology (2017)
Acta Haematologica (2017)
Fusion ofPDGFRBtoMPRIP, CPSF6, andGOLGB1in three patients with eosinophilia-associated myeloproliferative neoplasms
Genes, Chromosomes and Cancer (2015)
Molecular and Cellular Biology (2015)