REVIEW Myeloproliferative Disorders

REVIEW

Myeloproliferative disorders: the centrosome connection

B Delaval1, H Lelie`vre1 and D Birnbaum1

1Laboratory of Molecular Oncology, UMR599 Inserm, Marseille Cancer Institute, Institut Paoli-Calmettes, Marseille, France

Some myeloproliferative disorders (MPD) result from a recipro- BCR.10,11 Some consequences of the translocation have been cal translocation that involves the FGFR1 gene and a partner delineated. X-FGFR1 proteins contain both a constitutively gene. The event creates a chimeric gene that encodes a fusion activated FGFR1 TK and partner dimerisation motifs or protein with constitutive FGFR1 tyrosine kinase activity. 12–14 FGFR1-MPD is a rare disease, but its study may provide domains. They promote cell survival through signalling interesting clues on different processes such as cell signalling, pathways involving, among others, phospholipase C g (PLCg), oncogenesis and stem cell renewal. Some partners of FGFR1 phosphoinositol 3 kinase (PI3K), AKT and STAT proteins.12,15,16 are centrosomal proteins. The corresponding oncogenic fusion FGFR1-MDPs have been reproduced in mouse bone marrow kinases are targeted to the centrosome. Constitutive phosphor- transplantation models.17–19 ylation at this site may perturbate centrosome function and the cell cycle. Direct attack at this small organelle may be an Recent results have shown that at least two of the FGFR1 efficient way for oncogenes to alter regulation of signalling for partners, CEP1 and FOP, are bona fide centrosomal proteins. proliferation and survival and get rid of checkpoints in cell The centrosome, also called microtubule-organising centre cycle progression. The same effect might be triggered by other (MTOC), is a small cellular organelle essential for microtubule fusion kinases in other MPD and non-MPD malignancies. organisation and nucleation. CEP1 is a well-characterised Leukemia (2005) 19, 1739–1744. doi:10.1038/sj.leu.2403926; centrosomal protein20 with a coiled-coil structure and leucine published online 18 August 2005 Keywords: cell cycle; centrosome; myeloproliferative disorder; zipper motifs (Figure 2). It has no obvious orthologue in FGFR1; oncogene; tyrosine kinase 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 Although several issues remain to be clarified,1 molecular mechan- has a potential homologue in Arabdiopsis thaliana named isms of oncogenesis leading to malignant haemopathies have been tonneau. FOP, tonneau and various other eukaryotic proteins characterised.2 They frequently involve reciprocal chromosomal share a sequence motif of ca. 30-amino-acid residues named translocations, which schematically generate two classes of fusion LisH (lissencephaly homology domain). Human LisH-containing genes. The first class, found in acute myeloid leukaemias (AML), proteins LIS1/PAFAH1B1, TCOF1, OFD1 and TBL1X are mut- involves genes encoding transcription regulators; the fusion genes ated in Miller–Dieker lissencephaly, Treacher–Collins syndrome, promote cell survival and impair differentiation. The second class, orofacial-digital syndrome 1 and contiguous syndrome ocular found in myeloproliferative disorders (MPD), involves tyrosine albinism with late-onset sensorineural deafness, respectively.23 kinase (TK) genes; the resulting chimeric protein products are LIS1 protein is localised predominantly at the centrosome.24 constitutively activated TK that induce cell survival and prolifera- LisH is a thermodynamically very stable dimerisation domain25 tion. The BCR-ABL fusion was the first fusion TK to be characterised. that contributes to the regulation of microtubule dynamics, It is specific of chronic myelogenous leukaemia (CML), a frequent either by mediating dimerisation or by binding cytoplasmic typical MPD, and results from a t(9;22) translocation. dynein heavy chain or microtubules directly. MPDs are clonal haematological diseases that affect progenitor The centrosomal localisation of some FGFR1 partners led us cells; cells from the myeloid lineage, and sometimes from other to hypothesise that the corresponding X-FGFR1 fusion kinases lineages as well,3 proliferate continuously but, in contrast to may be addressed to the centrosome. The motif that targets CEP1 AML, undergo maturation. MPDs comprise typical MPDs (CML, to the centrosome is retained in the chimeric CEP1-FGFR1 polycythemia vera, essential thrombocythemia and idiopathic protein and this fusion product has therefore the potential to be myelofibrosis) and various other types of disorders. We have targeted to the centrosome.6 Indeed, our immunofluorescence represented in Figure 1 various fusions issued from chromosomal experiments localised FOP-FGFR1 and CEP1-FGFR1 at the rearrangements in MPDs. The FGFR1-MPD is a rare and centrosome in transfected Ba/F3 cells.22 FOP-FGFR1 also aggressive atypical MPD. It is also called stem cell MPD or localises at the centrosome in MPD mouse cells.22 Thus, the 8p12 (or 8p11) MPD because both lymphoid and myeloid FGFR1 partner protein does not only provide dimerisation lineages are affected following activation of the FGFR1 TK, which domain but also ensures specific addressing of the oncogenic is encoded by a gene on the p11–12 region of chromosome 8.4 kinase to a restricted site of action. Kinase attack at the centrosome

5 The FGFR1 gene is rearranged with several partners (designed Do malignant haemopathies show a general way once more? X thereafter), among which CEP1,6 FOP,7 ZNF1988,9 and How many MPDs are centrosomal diseases? Correspondence: Dr D Birnbaum, Laboratory of Molecular Oncology, UMR599 Inserm, Marseille Cancer Institute, Institut Paoli-Calmettes, A recent analysis of an FGFR1-MPD showed that a t(8;17) 232, 27 Bd. Leı¨ Roure, Marseille 13009, France; 26 Fax: þ 33 4 91 26 03 64; E-mail: [email protected] translocation resulted in an MYO18A-FGFR1 chimeric protein. Received 30 May 2005; accepted 26 July 2005; published online MYO18B, encoded by a paralogue of MYO18A, is found at the 18 August 2005 centrosome.21 Moreover, we have found that MYO18A interacts Myeloproliferative disorders: the centrosome connection B Delaval et al 1740 with CEP1 (L Daviet and D Birnbaum, unpublished). It is thus kinases of FGFR1-MPDs, have been found predominantly in likely that MYO18A-FGFR1, like FOP-FGFR1 and CEP1-FGFR1, the cytoplasm of cells using expressed GFP fusions. BCR-FGFR1 targets the centrosome. However, centrosomal localisation may is not directly targeted to the centrosome even if signalling could not be necessary to trigger the disease. ZNF198-FGFR1 and relay at this organelle.22 The recently discovered TIF1-FGFR1 BCR-FGFR1,10,12,14 the two other well-characterised fusion 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 Myome- galin has coiled coils such as that found in microtubule- Figure 1 Schematic summary of fusions resulting from transloca- associated proteins and a leucine zipper identical to that of tions associated to myeloproliferative disorders (MPD). Tyrosine Drosophila centrosomin.39 Both TRIP11 and myomegalin are kinases are represented by shaded squares, and protein partners by proteins of the Golgi/centrosome region. Myomegalin was circles. The FGFR1 gene is fused to ﬁve partners, including BCR. included in the list of centrosomal proteins detected by mass Reciprocally, BCR is the partner of four tyrosine kinase genes. In all, 21 10 different rearrangements of PDGF receptor B, and two of PDGF spectrometry. H4/CCDC6 is a coiled-coil protein that is also receptor A, have been characterised. Non-receptor-type tyrosine fused to the RET TK in thyroid carcinomas.40 Rabaptin 5 and kinases ABL, JAK2 and SYK are also involved in MPDs. BCR-ABL, HCMOGT1 have also coiled-coil domains; Rabaptin 5 is found which occurs in chronic myeloid leukaemia (CML) with t(9;22), is by in the endosomes. TP53BP1 controls the G2/M checkpoint.41 far the most frequent fusion. Proteins for which centrosomal FIP1L1 belongs to a polyadenylation complex. Recently, a new localisation is proven or is possible are represented by plain and fusion involving JAK2 kinase and centrosomal protein PCM1 has dotted grey circles, respectively. CMML: chronic myelomonocytic 42–44 leukaemia; CEL: chronic eosinophilic leukaemia; and HES: idiopathic been described in MPDs. Two other proteins very hypereosinophilic syndrome. frequently involved with TKs in MPDs are BCR and ETV6/TEL.

Figure 2 Schematic representation of the structure of partner proteins. Proteins fused to tyrosine kinases in myeloproliferative disorders are represented with their distinctive domains (as deﬁned by SMART program); small coiled-coil regions are not shown. Black arrows point to FGFR1-, JAK2-, and PDGFRB-MPD breakpoints, coloured arrows to breakpoints in other MPDs (CEL: chronic eosinophilic leukaemia; CML: chronic myeloid leukaemia; ALL: acute lymphoblastic leukaemia). BRCT: BRCA1 C-terminal repeats; ENTH: epsin NH2-terminal homology; FIP: FIP1 protein domain; KBD: kinetochore-binding domain; LisH: lissencephaly homology domain; LRR: leucine-rich repeats; MYM: myeloproliferative and mental retardation zinc-binding domain; PH: pleckstrin-homology domain; and PNT: pointed domain. In blue: coiled-coil motifs.

Leukemia Myeloproliferative disorders: the centrosome connection B Delaval et al 1741 Studies on the subcellular localisation of BCR and ETV6 have aneuploid and do not show ampliﬁcation of the centrosomes. If not suggested centrosomal localisation. X-FGFR1 proteins exert their oncogenic effect at the centro- Finally, in addition to fusion proteins, some cytoplasmic TKs some, it does not result in abnormal centrosome number and in might directly target the centrosome in the course of their aneuploidy. Another mechanism affecting centrosome function normal functions.45–47 This addressing may be conserved in an must be involved. oncogenic fusion.48 One of these kinases, JAK2, is constitutively Thus, in human haematological diseases, centrosomes may activated by point mutations in MPD.49–52 Fused or mutated, not only show ampliﬁcation leading to chromosomal instability these TKs might affect the cell cycle through, among other and aneuploidy but also alteration of function without alteration possibilities, an altered centrosomal function. in number. This might be true for other cancers as well.

A model for leukaemogenesis, perhaps more

We have proposed that some TK alterations target the What could be the effects of a centrosomal oncogenic kinase centrosome and lead to MPD. Translocation-activated TKs are on centrosome function? found in other types of cancer, in particular lymphomas and sarcomas.53 The ALK TK receptor is involved in both anaplastic The presence of a constitutively active X-FGFR1 kinase at the lymphomas and inflammatory myofibroblastic tumours. Centro- centrosome may affect several processes associated with the some abnormalities are observed in ALK-positive lympho- function of this organelle. More than just an MTOC, the mas.54,55 The preferred partner of ALK is nucleophosmin centrosome is important for the regulation of cell cycle (NPM1). A recent study has shown that nucleophosmin is progression.68–70 It also influences cell shape, polarity and mutated in AMLs.56 At some periods of the cell cycle, motility and is linked to DNA repair.71,72 Accordingly, many nucleophosmin transits through the centrosome. Thus, NPM1- proteins involved in these processes are found at the centro- ALK fusion kinase and mutated NPM1 may perturbate processes some, including cyclins, BRCA1, P53, and various kinases, associated with centrosome function. Another protein involved phosphatases, signalling substrates and cell cycle regula- in oncogenic fusion is PML. PML has also been found at the tors.21,73 Our recent results indicate that X-FGFR1 at the centrosome recently.57 Centrosome alteration might also occur centrosome deregulates G1/S events, and particularly the in epithelial cancers, in which some examples of translocations restriction point from G1-phase to S-phase, when centrosome leading to chimeric TK activation have been described.40,58,59 duplication occurs.22 Abnormal activation of X-FGFR1 at the However, all fusion proteins will not target the centrosome. centrosome may affect the regulation of various molecular Still, some of the oncogenic kinases that are not addressed to the complexes. It may activate a proliferation signal at the centrosome may target subcellular sites that are involved in the centrosome, relieve a brake on the cell cycle, and simulta- control of cell division in coordination with this organelle, for neously perturbate apoptosis in the targeted stem cell, which example, the Golgi apparatus or the nucleolus, or may use some would subsequently survive and divide continuously. Directly relays at the centrosome, as suggested for BCR-FGFR1.22 The targeting a constitutively active kinase to the centrosome could centrosome is linked either directly or via microtubule tracks to activate and/or recruit key regulators of cell cycle such as many other subcellular areas, and signalling may transit through cyclins. Several potential processes can be affected such as the centrosome via vesicular transport. Oncogenes may thus regulation of transcription, cell cycle regulator recruitment or target the centrosome from the distance. 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 Numerical and functional alterations of the centrosome activating known core centrosomal proteins (eg CAP350, in cancer centrin) or cell cycle regulators such as RB1, cyclins, CDKs or CDK inhibitors. Centrosome alterations are frequent in various types of cancer, Centrosome duplication is tightly coordinated with chromo- including haematological diseases.60 In normal conditions, the some duplication and cell cycle entry. To allow constitutive centrosome undergoes duplication precisely once per cell entry in S-phase, the ectopic fusion TK may directly activate division during the G1/S transition. Centrosome amplification, centrosome duplication, which is initiated at the G1/S transition which can result from disruption, cell fusion, overduplication, of the cell cycle and completed before mitosis. This could occur de novo formation or aborted cell division,61,62 has been by phosphorylation and direct activation of downstream kinases described as a major cause of aneuploidy.63 In AMLs, both (CDK2, PLK, JNK, PI3K) and/or other signalling proteins structural and numerical chromosome aberrations are frequent important for centrosome duplication.72 PI3K for example, a and provide diagnostic and prognostic information.64 Structural known X-FGFR1 downstream target, is involved in centrosome and numerical alterations of centrosomes are also common in duplication.72 Cyclins D, and cyclin E/CDK2 complex, which is non-Hodgkin’s lymphomas and may contribute to the chromo- involved in both the coordination of DNA replication and somal instability typically seen in these diseases.65 It is worth centrosome duplication, would constitute good targets for noting here that Hodgkin’s lymphomas frequently show X-FGFR1 kinase. Cyclin E centrosomal localisation is important amplification of the JAK2 gene region.66 Structural and to accelerate S-phase entry.74 numerical centrosomal abnormalities have also recently been Finally, FGFR1 fusion partners, because they are centrosomal described in CML; they correlate with the stage of the disease proteins, may not only provide neutral dimerisation domains and chromosomal instability.67 and addressing motifs but could also participate actively to the MPD cells are not particularly aneuploid at the chronic phase. oncogenic process. A bidirectional oncogenic effect could thus The translocation that generates the chimeric TK gene is often be created, one through constitutive TK activation, and the other the only karyotypic abnormality. Moreover, cells overexpressing one through disruption of partner function. However, there is no an X-FGFR1 fusion kinase in experimental systems are not evidence in support of this hypothesis.

Leukemia Myeloproliferative disorders: the centrosome connection B Delaval et al 1742 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 Figure 3 Potential effects of centrosomal oncogene on stem cell through the centrosome. We believe that not only this small fate. In normal haematopoiesis, stem cells stimulated to divide enter organelle is associated with cell division through the organisa- the cell cycle and evade apoptotic signals; they give birth through tion of microtubules but that it also deals directly with the asymmetric division to progenitors engaged in differentiation and to signals associated with this process. In other words, the new stem cells. In myeloproliferative disorder with centrosomal fusion centrosome might integrate various signalling pathways aimed kinase, entry of stem cells in the proliferating pool in sustained and apoptosis is prevented. This could occur at any stage. Arrows: at triggering cell division. Many signalling molecules, such as potential effects of MPD kinase; arrow 1: cell cycle entry; and arrow PI3K, PLCg, MAP kinases and AKT, are found at the centro- 2: cell survival. some.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 MPDs and continuous proliferation: molecular understanding affected in MPD. It is directly involved in the control of the cell of precancerous lesions? cycle in regulating G1 cyclins D1 and E.76 Degradation of cyclin D1 upon GSK3b phosphorylation is inhibited by the AKT The study of FGFR1-MPD can perhaps teach us other general pathway. Pools of both AKT and GSK3b are found at the lessons. MPD is characterised by survival and proliferation. centrosome.77 Similarly, the FGFR1 signalling pathway upregu- Survival is intrinsic to stem cell biology and, as we have lates D cyclins.78 NIN, a fusion partner of PDGFRB in MPD, proposed for FOP-FGFR1, proliferation is due to sustained G1/S interacts with GSK3 kinase. transition and triggering of centrosome duplication. Apart from Owing to its location in the cytoplasm, at the crossroads of these characteristics, the MPD proliferating cell is quite normal microtubules, close to the nucleus and the proteasome, and and does not show extensive genome mutations and mitotic connected to the Golgi apparatus, the centrosome as an defects. One alteration (eg a mutation or translocation in the ‘integrating centre’ can be an easy prey for pathogens in various case of an MPD), leading to the perturbation of centrosome- diseases. Directly attacking this organelle could be a convenient associated processes, is sufﬁcient to affect the G1/S transition way for oncogenes, mutated regulators (eg NPM), fusion kinases and trigger proliferation. We believe these mechanisms will be (eg FOP-FGFR1, NIN-PDGFRB, PCM1-JAK2) and viral pro- found in other if not all cell proliferations associated with teins79 to perturbate signalling pathways normally leading to hyperplasia and precancerous states. In that sense, MPDs might regulated cell survival, cell proliferation and cell division, also be considered, at the very beginning of the disease, as especially if this occurs in stem cells. It may one day become precancerous states. Secondary alterations, associated with interesting to design drugs that target proteins speciﬁcally at the other periods and checkpoints of the cell cycle, subsequently centrosome. generate genome instability and aneuploidy, and trigger the full spectrum of malignant cell chaos.

The centrosome: a trigger for stem cells to enter the cell cycle? Acknowledgements

MPDs are diseases of haematopoietic progenitors. Characterisa- Work in our laboratory on MPD is supported by Inserm, Institut tion of the mechanisms that induce sustained cycling of these Paoli-Calmettes, Association Laurette Fugain and Ministries of cells is important for our understanding of stem cell biology. The Health and Research (Cance´ropoˆle). BD has been successively centrosome may serve as a trigger for the stem cell to enter the supported by Ministry of Research, Ligue Nationale Contre le cell cycle. Here again, the PI3K-AKT pathway could play an Cancer and Socie´te´ Franc¸aise d’He´matologie. 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 References pathogenesis (Figure 3). The centrosomal fusion kinase, which deregulates and overcomes checkpoint arrest allowing consti- 1 Passegue´ E, Jamieson CH, Ailles LE, Weissman IL. Normal and tutive G1/S progression, may affect the process of asymmetric leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA division. We cannot exclude that centrosomal kinases also 2003; 100 (Suppl. 1): 11842–11849. induce G0/G1 progression in stem cells, but it remains to be 2 Gilliland DG. Molecular genetics of human leukemias: new demonstrated. insights into therapy. Semin Hematol 2002; 39: 6–11.

Leukemia Myeloproliferative disorders: the centrosome connection B Delaval et al 1743 3 Murati A, Arnoulet C, Lafage-Pochitaloff M, Ade´laı¨de J, Derre´ M, 22 Delaval B, Le´tard S, Lelie`vre H, Chevrier V, Daviet L, Dubreuil P Slama B et al. Dual lympho-myeloproliferative disorder in a patient et al. oncogenic kinase of malignant hemopathy targets the with t(8;22) with BCR-FGFR1 gene fusion. Int J Oncol 2005; 26: centrosome. Cancer Res 2005; 65 (in press). 1485–1492. 23 Emes RD, Ponting CP. A new sequence motif linking lissence- 4 Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic phaly, Treacher–Collins and oral-facial-digital type 1 syndromes, myeloproliferative diseases. Leukemia 2002; 16: 1207–1212. microtubule dynamics and cell migration. Hum Mol Genet 2001; 5 Chaffanet M, Popovici C, Leroux D, Jacrot M, Ade´laı¨de J, Dastugue 10: 2813–2820. N et al. t(6;8), t(8;9) and t(8;13) translocations associated with 24 Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, stem cell myeloproliferative disorders have close or identical Gleeson JG. Lis1 and doublecortin function with dynein to mediate breakpoints in chromosome region 8p11–12. Oncogene 1998; 16: coupling of the nucleus to the centrosome in neuronal migration. 945–949. J Cell Biol 2004; 165: 709–721. 6 Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, 25 Kim MH, Cooper DR, Oleksy A, Devedjiev Y, Derewenda U, Rattner JB et al. FGFR1 is fused to the centrosome-associated Reiner O et al. The structure of the N-terminal domain of the protein CEP110 in the 8p12 stem cell myeloproliferative disorder product of the lissencephaly gene Lis1 and its functional with t(8;9)(p12;q33). Blood 2000; 95: 1788–1796. implications. Structure (Cambridge) 2004; 12: 987–998. 7 Popovici C, Zhang B, Gre´goire MJ, Jonveaux P, Lafage-Pochitlaoof 26 Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Hochhaus A M, Birnbaum D et al. The t(6;8)(q27;p11) translocation in a stem et al. The t(8;17)(p11;q23) in the 8p11 myeloprolifera- cell myeloproliferative disorder fuses a novel gene, FOP, to tive syndrome fuses MYO18A to FGFR1. Leukemia 2005; 19: fibroblast growth factor receptor 1. Blood 1999; 93: 1381–1389. 1005–1009. 8 Popovici C, Ade´laide J, Ollendorff V, Chaffanet M, Guasch G, 27 Belloni E, Trubia M, Gasparini P, Mecucci C, Tapinassi C, Jacrot M et al. Fibroblast growth factor receptor 1 is fused to FIM in Confalioneri S et al. 8p11 myeloproliferative syndrome with a stem-cell myeloproliferative disorder with t(8;13). Proc Natl Acad novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 Sci USA 1998; 95: 5712–5717. genes. Genes Chromosomes Cancer 2005; 42: 320–325. 9 Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES 28 Vizmanos JL, Novo FJ, Roman JP, Baxter EJ, Lahortiga I, Odero MD et al. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in et al. NIN, a gene encoding a CEP110-like centrosomal protein, is the t(8;13) leukaemia/lymphoma syndrome. Nat Genet 1998; 18: fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an 84–87. imatinib-responsive myeloproliferative disorder. Cancer Res 2004; 10 Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen SL et al. 64: 2673–2676. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: 29 Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H. transforming activity and specific inhibition of FGFR1 fusion Fusion of the platelet-derived growth factor receptor b to a novel proteins. Blood 2001; 98: 3778–3783. gene CEV14 in acute myelogenous leukemia after clonal evolu- 11 Fioretos T, Panagopoulos I, Lassen C, Swedin A, Billstrom R, tion. Blood 1997; 90: 4271–4277. Isaksson M et al. Fusion of the BCR and the fibroblast growth factor 30 Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a et al. Fusion of H4/D10S170 to the platelet-derived growth myeloproliferative disorder: the first fusion gene involving BCR but factor receptor beta in BCR-ABL-negative myeloprolifera- not ABL. Genes Chromosomes Cancer 2001; 32: 302–310. tive disorders with a t(5;10)(q33;q21). Cancer Res 2000; 60: 12 Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, 3592–3598. Pe´busque MJ. Characterization of FIM-FGFR1, the fusion product 31 Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger LA, of the myeloproliferative disorder-associated t(8;13) translocation. Barrett AJ et al. Rabaptin-5 is a novel fusion partner to platelet- J Biol Chem 1999; 274: 26922–26930. derived growth factor beta receptor in chronic myelomonocytic 13 Xiao S, McCarthy JG, Aster JC, Fletcher J. ZNF198-FGFR1 leukemia. Blood 2001; 98: 2518–2525. transforming activity depends on a novel proline-rich ZNF198 32 Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, Locatelli F oligomerization domain. Blood 2000; 96: 699–704. et al. HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile 14 Baumann H, Kunapuli P, Tracy E, Cowell JK. The oncogenic fusion myelomonocytic leukemia with t(5;17)(q33;p11.2). Cancer Res protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 2004; 64: 2649–2651. has signaling function comparable with interleukin-6 cytokine 33 Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA et al. receptors. J Biol Chem 2003; 278: 16198–16208. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder 15 Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pe´busque MJ. 8p12 associated with eosinophilia: involvement of PDGFRB and stem cell myeloproliferative disorder: the FOP-fibroblast growth response to imatinib. Blood 2003; 102: 4187–4190. factor receptor 1 fusion protein of the t(6;8) translocation induces 34 Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, cell survival mediated by mitogen-activated protein kinase and Stone RM et al. KIAA1509 is a novel PDGFRB fusion partner in phosphatidylinositol 3-kinase/Akt/mTOR pathways. Mol Cell Biol imatinib-responsive myeloproliferative disease associated with a 2001; 21: 8129–8142. t(5;14)(q33;q32). Leukemia 2005; 19: 27–30. 16 Heath C, Cross NC. Critical role of STAT5 activation in 35 Grand FH, Burgstaller S, Kuhr T, Baxter EJ, Webersinke G, Thaler J transformation mediated by ZNF198-FGFR1. J Biol Chem 2004; et al. P53-binding protein 1 is fused to the platelet-derived growth 279: 6666–6673. factor receptor beta in a patient with a t(5;15)(q33;q22) and 17 Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M an imatinib-responsive eosinophilic myeloproliferative disorder. et al. PKC412 inhibits the zinc finger 198-fibroblast growth factor Cancer Res 2004; 64: 7216–7219. receptor 1 fusion tyrosine kinase and is active in treatment of stem 36 Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutre SE cell myeloproliferative disorder. Proc Natl Acad Sci USA 2004; et al. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hyper- 101: 14479–14484. eosinophilic syndrome and chronic eosinophilic leukemia: im- 18 Guasch G, Delaval B, Arnoulet C, Xie MJ, Xerri L, Sainty D et al. plications for diagnosis, classification, and management. Blood FOP-FGFR1 tyrosine kinase, the product of a t(6;8) translocation, 2004; 103: 2879–2891. induces a fatal myeloproliferative disease in mice. Blood 2004; 37 Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, 103: 309–312. Vanstraelen D et al. Clinical and molecular features of FIP1L1- 19 Roumiantsev S, Krause DS, Neumann CA, Dimitri CA, Asiedu F, PDFGRA (+) chronic eosinophilic leukemias. Leukemia 2004; 18: Cross NC et al. Distinct stem cell myeloproliferative/T lymphoma 734–742. syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion 38 Infante C, Ramos-Morales F, Fedriani C, Bornens M, Rios RM. genes from 8p11 translocations. Cancer Cell 2004; 5: 287–298. GMAP-210, a cis-Golgi network-associated protein, is a minus 20 Ou YY, Mack GJ, Zhang M, Rattner JB. CEP110 and ninein are end microtubule-binding protein. J Cell Biol 1999; 145: located in a specific domain of the centrosome associated with 83–98. centrosome maturation. J Cell Sci 2002; 115: 1825–1835. 39 Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D et al. 21 Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann Myomegalin is a novel protein of the Golgi/centrosome that M. Proteomic characterization of the human centrosome by interacts with a cyclic nucleotide phosphodiesterase. J Biol Chem protein correlation profiling. Nature 2003; 426: 570–574. 2001; 276: 11189–11198.

Leukemia Myeloproliferative disorders: the centrosome connection B Delaval et al 1744 40 Alberti L, Carniti C, Miranda C, Roccato E, Pierotti MA. RET and primary event in human secretory breast carcinoma. Cancer Cell NTRK1 proto-oncogenes in human diseases. J Cell Physiol 2003; 2002; 2: 367–376. 195: 168–186. 60 Kramer A, Neben K, Ho AD. Centrosomal aberrations in 41 Wang B, Matsuoka S, Carpenter PB, Elledge SJ. 53BP1, a mediator hematological malignancies. Cell Biol Int 2005; 29: 376–384. of the DNA damage checkpoint. Science 2002; 298: 1435–1438. 61 Nigg EA. Centrosome aberrations: cause or consequence of cancer 42 Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B progression? Nat Rev Cancer 2002; 2: 815–825. et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and 62 Storchova Z, Pellman D. From polyploidy to aneuploidy, genome acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: instability and cancer. Nat Rev Mol Cell Biol 2004; 5: 45–54. 2662–2667. 63 Brinkley BR. Managing the centrosome numbers game: from 43 Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B, chaos to stability in cancer cell division. Trends Cell Biol 2001; 11: Delsol G et al. The t(8;9)(p22;p24) translocation in atypical 18–21. chronic myeloproliferative disorders yields a new PCM1-JAK2 64 Neben K, Tews B, Wrobel G, Hahn M, Kokocinski F, Giesecke C fusion gene. Oncogene (in press). et al. Gene expression patterns in acute myeloid leukemia 44 Murati A, Gelsi-Boyer V, Ade´laı¨de J, Perot C, Talmant P, Giraudier correlate with centrosome aberrations and numerical chromosome S et al. PCM1-JAK2 fusion in myeloproliferative disorders and changes. Oncogene 2004; 23: 2379–2384. acute erythtroid leukemia with t(8;9) translocation. Leukemia 65 Kramer A, Schweizer S, Neben K, Giesecke C, Kalla J, 2005, 21 July [E-pub ahead of print]. Katzenberger T et al. Centrosome aberrations as a possible 45 Faruki S, Geahlen RL, Asai DJ. Syk-dependent phosphorylation of mechanism for chromosomal instability in non-Hodgkin’s lym- microtubules in activated B-lymphocytes. J Cell Sci 2000; 113: phoma. Leukemia 2003; 17: 2207–2213. 2557–2565. 66 Joos S, Kupper M, Ohl S, von Bonin F, Mechtersheimer C, Bentz M 46 Takahashi S, Inatome R, Hotta A, Qin Q, Hackenmiller R, Simon et al. Genomic imbalances including amplification of the tyrosine MC et al. Role for Fes/Fps tyrosine kinase in microtubule kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res 2000; 60: nucleation through is Fes/CIP4 homology domain. J Biol Chem 549–552. 2003; 278: 49129–49133. 67 Giehl M, Fabarius A, Frank O, Hochhaus A, Hafner M, Hehlmann 47 Steindler C, Li Z, Algarte M, Alcover A, Libri V, Ragimbeau J R et al. Centrosome aberrations in chronic myeloid leukemia et al. Jamip1 (marlin-1) defines a family of proteins interacting correlate with stage of disease and chromosomal instability. with janus kinases and microtubules. J Biol Chem 2004; 279: Leukemia 2005; 19: 1192–1197. 43168–43177. 68 Hinchcliffe EH, Miller FJ, Cham M, Khodjakov A, Sluder G. 48 Kuno Y, Abe A, Emi N, Iida M, Yokozawa T, Towatari M et al. Requirement of a centrosomal activity for cell cycle progression Constitutive kinase activation of the TEL-Syk fusion gene in through G1 into S phase. Science 2001; 291: 1547–1550. myelodysplastic syndrome with t(9;12)(q22;p12). Blood 2001; 69 Khodjakov A, Rieder CL. Centrosomes enhance the fidelity of 97: 1050–1055. cytokinesis in vertebrates and are required for cell cycle 49 Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S progression. J Cell Biol 2001; 153: 237–242. et al. Acquired mutation of the tyrosine kinase JAK2 in human 70 Rieder CL, Faruki S, Khodjakov A. The centrosome in vertebrates: myeloproliferative disorders. Lancet 2005; 365: 1054–1061. more than a microtubule-organizing center. Trends Cell Biol 2001; 50 Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR 11: 413–419. et al. A gain-of-function mutation of JAK2 in myeloproliferative 71 Griffin CS. Aneuploidy, centrosome activity and chromosome disorders. N Engl J Med 2005; 352: 1779–1790. instability in cells deficient in homologous recombination repair. 51 Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ Mutat Res 2002; 504: 149–155. et al. Activating mutation in the tyrosine kinase JAK2 in 72 Wang Q, Hirohashi Y, Furuuchi K, Zhao H, Liu Q, Zhang H et al. polycythemia vera, essential thrombocythemia, and myeloid The centrosome in normal and transformed cells. DNA Cell Biol metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397. 2004; 23: 475–489. 52 James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C 73 D’Assoro AB, Lingle WL, Salisbury JL. Centrosome amplification et al. A unique clonal JAK2 mutation leading to constitu- and the development of cancer. Oncogene 2002; 21: 6146–6153. tive signalling causes polycythaemia vera. Nature 2005; 434: 74 Matsumoto Y, Maller JL. A centrosomal localization signal in 1144–1148. cyclin E required for Cdk2-independent S phase entry. Science 53 Tuveson DA, Fletcher JA. Signal transduction pathways in sarcoma 2004; 306: 885–888. as targets for therapeutic intervention. Curr Opin Oncol 2001; 13: 75 Massague J. G1 cell-cycle control and cancer. Nature 2004; 432: 249–255. 298–306. 54 Kutok JL, Aster JC. Molecular biology of anaplastic lymphoma 76 Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock kinase-positive anaplastic large-cell lymphoma. J Clin Oncol WL et al. Involvement of PI3K/Akt pathway in cell cycle 2002; 20: 3691–3702. progression, apoptosis, and neoplastic transformation: a target for 55 Ventura RA, Martin-Subero JI, Knippschild U, Gascoyne RD, cancer chemotherapy. Leukemia 2003; 17: 590–603. Delsol G, Mason DY et al. Centrosome abnormalities in ALK- 77 Wakefield JG, Stephens DJ, Tavare JM. A role for glycogen positive anaplastic large-cell lymphoma. Leukemia 2004; 18: synthase kinase-3 in mitotic spindle dynamics and chromosome 1910–1911. alignment. J Cell Sci 2003; 116: 637–646. 56 Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L 78 Koziczak M, Holbro T, Hynes NE. Blocking of FGFR signaling et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia inhibits breast cancer cell proliferation through downregulation of with a normal karyotype. N Engl J Med 2005; 352: 254–266. D-type cyclins. Oncogene 2004; 23: 3501–3508. 57 Xu ZX, Zou WX, Lin P, Chang KS. A role for PML3 in centrosome 79 Mu¨nger K, Duensing S. Human papillomavirus infection and duplication and genome stability. Mol Cell 2005; 17: 721–732. centrosome anomalies in cervical cancer. In: Nigg E (ed). 58 Corvi R, Berger N, Balczon R, Romeo G. RET/PCM-1: a novel Centrosomes in Development and Disease. New York: Wiley- fusion gene in papillary thyroid carcinoma. Oncogene 2000; 19: VCH, 2004, pp 353–370. 4236–4242. 80 Paling NR, Wheadon H, Bone HK, Welham MJ. Regulation of 59 Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk M, embryonic stem cell self-renewal by phosphoinositide 3-kinase- Mathers JA et al. Expression of the ETV6-NTRK3 gene fusion as a dependent signaling. J Biol Chem 2004; 279: 48063–48070.

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