Leukemia (2005) 19, 1739–1744. doi:10.1038/sj.leu.2403926; published online 18 August 2005

Myeloproliferative disorders: the centrosome connection

B Delaval1, H Lelièvre1 and D Birnbaum1

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

Correspondence: Dr D Birnbaum, Laboratory of Molecular Oncology, UMR599 Inserm, Marseille Cancer Institute, Institut Paoli-Calmettes, 232, 27 Bd. Leï Roure, Marseille 13009, France. Fax: +33 4 91 26 03 64; E-mail:

Received 30 May 2005; Accepted 26 July 2005; Published online 18 August 2005.



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.


cell cycle, centrosome, myeloproliferative disorder, FGFR1, oncogene, tyrosine kinase

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

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Schematic summary of fusions resulting from translocations associated to myeloproliferative disorders (MPD). Tyrosine kinases are represented by shaded squares, and protein partners by circles. The FGFR1 gene is fused to five partners, including BCR. Reciprocally, BCR is the partner of four tyrosine kinase genes. In all, 10 different rearrangements of PDGF receptor B, and two of PDGF receptor A, have been characterised. Non-receptor-type tyrosine kinases ABL, JAK2 and SYK are also involved in MPDs. BCR-ABL, which occurs in chronic myeloid leukaemia (CML) with t(9;22), is by far the most frequent fusion. Proteins for which centrosomal localisation is proven or is possible are represented by plain and dotted grey circles, respectively. CMML: chronic myelomonocytic leukaemia; CEL: chronic eosinophilic leukaemia; and HES: idiopathic hypereosinophilic syndrome.

Full figure and legend (81K)


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 italic gamma (PLCitalic gamma), 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.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

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.

Full figure and legend (143K)

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, PLCitalic gamma, 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 GSK3beta phosphorylation is inhibited by the AKT pathway. Pools of both AKT and GSK3beta 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.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Potential effects of centrosomal oncogene on stem cell fate. In normal haematopoiesis, stem cells stimulated to divide enter the cell cycle and evade apoptotic signals; they give birth through asymmetric division to progenitors engaged in differentiation and to new stem cells. In myeloproliferative disorder with centrosomal fusion kinase, entry of stem cells in the proliferating pool in sustained and apoptosis is prevented. This could occur at any stage. Arrows: potential effects of MPD kinase; arrow 1: cell cycle entry; and arrow 2: cell survival.

Full figure and legend (84K)


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.



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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.