Human Molecular Genetics

Human Molecular Genetics 2005 14(Review Issue 1):R93-R100; doi:10.1093/hmg/ddi111

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Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors

Frank M. Raaphorst^*

Department of Pathology, VU Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

^* To whom correspondence should be addressed. Email: fm.raaphorst{at}vumc.nl

Received January 17, 2005; Accepted February 17, 2005

	ABSTRACT

TOP ABSTRACT POLYCOMB GENES, PROTEINS AND... MECHANISTIC ASPECTS OF GENE... PcG GENES AND THE... PcG ONCOGENE EXPRESSION IN... PcG ONCOGENE EXPRESSION IN... CONCLUDING REMARKS REFERENCES

 
Genes belonging to the Polycomb-group (PcG) are epigenetic gene silencers with a vital role in the maintenance of cell identity. They contribute to regulation of various processes in both embryos and adults, including the cell cycle and lymphopoiesis. A growing body of work has linked human PcG genes to various hematological and epithelial cancers, identifying novel mechanisms of malignant transformation and paving the way to development of new cancer treatments and identification of novel diagnostic markers. This review addresses the current insights in the role of PcG genes in development of human malignancies.

	POLYCOMB GENES, PROTEINS AND COMPLEXES

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Polycomb-group (PcG) genes play a vital role in stable inheritance of tissue- and cell type-specific gene silencing patterns and are responsible for maintenance of cellular identity through many successive cell generations. PcG genes were first discovered as epigenetic gene silencers during embryogenesis and have been found to play a role in development of the heart (1,2), the skeleton (3–5) and the nervous system (6,7). However, PcG genes play a central role in regulation of various adult processes, including the cell cycle, lymphopoiesis and X-inactivation (8), and several PcG genes have been identified as oncogenes.

PcG proteins use conserved protein domains to form multimeric complexes (Table 1) (reviewed in 9–13). In humans, the Polycomb repressive complex 1 (PRC1) contains the BMI1/MEL18, RING, HPC and HPH PcG proteins. Another complex, PRC2, is composed of EED, EZH, SUZ12 and YY1. These proteins represent the evolutionary conserved complex ‘core’, but the fine composition of PcG complexes is determined by cell type and tissue type and by proliferation status (10,14–17). Several PcG proteins interact or colocalize with various non-PcG proteins, including the transcription modulators CtBP (18), E2F6 (14,19), KyoT2 (20), RYBP (21), AF9 (22), SSX (23) and the MAP/KAP kinase 3pK (24). All of these proteins may contribute to the silencing activity of PcG complexes and their ability to bind chromatin, and many are involved in oncogenesis.

View this table: [in this window] [in a new window]   Table 1. Human Polycomb-group genes and proteins

 

	MECHANISTIC ASPECTS OF GENE SUPPRESSION BY PcG COMPLEXES

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PcG complexes bind chromatin and are directly involved in remodeling of chromatin structure and, as a consequence, control of gene activity. Two of the best-known forms of chromatin modification are histone tail acetylation and methylation, which, as a rule-of-thumb, result in gene activation and silencing, respectively (25). PcG complexes associate with, or contain, various enzymes that modify histone tails, including histone deacetylases (HDACs), histone methyl transferases (HMTs) and an ubiquitin ligase (Table 1). In PRC2, the EED protein recruits the HDAC1/2 HDACs (26), whereas EZH2 is a known HMT that methylates lysine 27 of histone H3 (27–29). The other PcG complex, PRC1, is associated with HMT activity and contains CBX4/HPC2, which has SUMO E3 ligase activity, and RING1/RNF2, which are E3 ubiquitin ligases that ubiquitinate lysine 119 of histone H2A (30–34). Most of these enzymatic activities are evolutionary conserved (35–38), and transcriptional silencing of PcG target genes is closely linked to introduction of ‘epigenetic marks’ such as methylated lysine residues on histone tails (39–41). In addition, interference with key components of PcG complexes removes these epigenetic marks and relieves repression of PcG target genes (39,42). It is now commonly accepted that alteration of chromatin structure is the main mode of action of PcG complexes.

A hypothetical mechanism of PcG-mediated gene silencing (reviewed in 9,10) proposes that maintenance of gene silencing requires both PcG complexes. This process is initiated by HDAC activity of the PRC2 ‘initiation’ complex, which deacetylates core histone tails. This is followed by methylation of these residues, most likely through HMT activity of EZH2 in PRC2. Experiments in Drosophila demonstrated transient interaction between components of the two complexes at the time when silencing is established (43). Also, methylated histone 3 tails are thought to form a docking site for the PRC1 ‘maintenance’ complex. Recruitment of the PRC1 complex may lead to additional methylation by the SUV39H1 HMT in PRC1 and establishment of a stable pattern of gene suppression.

	PcG GENES AND THE CELL CYCLE

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PcG genes are the focus of intense scientific scrutiny because of their direct role in cell cycle control and malignant transformation (Table 2). The best-known example is regulation by the Bmi1 PcG protein of a major cell cycle checkpoint in which the inhibitors p16^INK4A and p19^ARF (p14^ARF in humans) play a central role. Lymphocytes in mice with transgenic overexpression of Bmi1 downregulate p16^INK4A and p19^ARF and have a high predisposition for B- and T-cell lymphomas (44–48). This observation directly links the PRC1 complex, containing Bmi-1, to regulation of apoptosis and senescence in mice. During normal cell cycle control, the retinoblastoma (Rb) gene product is hyperphosphorylated (pRb) by the complex of cyclin D and cyclin-dependent kinases 4 and 6 (Cdk4/6). Rb normally binds to the E2F transcription factor, but pRb is unable to do so and allows transcription of E2F-dependent promoters. This results in cell cycle progression because genes that are necessary for the G1/S transition are transcribed. The role of p16^INK4A in this process is such that it prevents binding of Cdk4/6 to cyclin D and thereby inhibits phosphorylation of Rb, resulting in inhibition of E2F-mediated transcription, cycle arrest and senescence. In addition, p19^ARF inhibits p53 degradation by sequestering MDM2, which results in p53-mediated cell cycle arrest and apoptosis.

View this table: [in this window] [in a new window]   Table 2. Expression of selected Polycomb-group genes in cancers and proposed role in malignant transformation

 
These observations have produced a model of cell cycle regulation by the PRC1 protein Bmi1, where Bmi1 downregulates p16^INK4A and p19^ARF. This results in cell cycle progression because Rb is hyperphosphorylated and p53 is degraded. Notably, in the absence of Bmi1, p16^INK4A and p19^ARF are upregulated and cells become subject to apoptosis/senescence pathways (7, 48). Although these observations suggest that the PRC1 complex is the main player in regulation of the cell cycle, evidence is rapidly increasing that the PRC2 complex is intricately involved in this process as well. For instance, overexpression of the PRC2 EZH2 gene in human breast epithelial cell lines promoted transformation and conferred invasive capacity (49), demonstrating that transformation capacity is not limited to PRC1. The situation becomes even more complex by the discovery that the PRC2 genes EZH2 and EED are themselves downstream target genes of the E2F–pRb pathway (50,51), suggesting that the PRC1 complex may contribute to regulation of components of PRC2.

The development of malignant lymphomas in Bmi1-transgenic animals and the transforming capability of Bmi1 in primary MEFs immediately raise the question of whether human BMI-1 possibly contributes to development of cancer by a similar mechanism. One indication that it may indeed contribute to oncogenesis came from studies of primary human fibroblasts, where overexpression of BMI1 resulted in an extended replicative lifespan by inhibition of p16^INK4A (52). Although BMI1 overexpression did not result in immortalization of the fibroblasts, similar studies in mammary epithelial cells demonstrated that experimental overexpression of BMI1 produced elevated telomerase activity and immortalization (53), suggesting that BMI1 can contribute to malignant transformation by multiple mechanisms which are cell type-specific.

These studies, and the work in mutant mice, collectively identified BMI1 and EZH2 as bona fide oncogenes with cell type-specific transforming capabilities and have naturally placed these genes in the spotlight of cancer research in humans. However, the extent to which artificial overexpression of these genes in cell models reflects the situation in patients is unclear. However, a rapidly growing body of work, has demonstrated that neoplastic cells in various human cancers all display abnormal patterns of PcG gene expression.

	PcG ONCOGENE EXPRESSION IN HUMAN MALIGNANT LYMPHOMAS

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Altered PcG gene expression is widespread in human malignant lymphomas, and neoplastic cells in primary nodal large B-cell lymphomas (LBCL) (54,55), mantle cell lymphomas (MCL) (56,57) and Hodgkin's lymphoma (HL) (58–60) abnormally express BMI1 and several of its PRC1 binding partners. In the normal counterparts of these malignancies, the mature B-cells in germinal centers (GC), expression of the majority of PcG genes encoding PRC1 and PRC2 is separated in resting and activated cells (16,61,62). For instance, BMI1 and several of its binding partners in PRC1 are primarily detected in resting B-cells in the GC mantle zone and in non-dividing centrocytes of the GC follicle. In contrast, these genes appear silent in proliferating follicular centroblasts which express the PRC2 genes EZH2 and EED instead. However, cycling neoplastic cells in human malignant lymphomas have lost the mutually exclusive expression of core components of PRC1 and PRC2. These cells coexpress all PcG proteins constituting the PRC1 and PRC2 complexes, suggesting an inability to downregulate the PRC1 complex during cell division (55,56,58,59).

Aberrant BMI1 expression in cycling neoplastic cells of malignant lymphomas correlates well with development of lymphomas in Bmi1 transgenic mice and strongly suggests that human BMI1 contributes to lymphomagenesis. This is supported by the distinct expression patterns of individual PRC1 PcG genes in clinically defined primary LBCL subgroups (55) and their close correlation with biological behavior (63–66). For instance, dividing neoplastic cells in primary nodal LBCL overexpress BMI1 and several of its binding partners and have an unfavorable to intermediate prognosis (55). In contrast, primary cutaneous LBCL have a better prognosis and express these binding partners as well, but in the absence of BMI1. Also, re-analysis of a previously published database of gene expression in diffuse LBCL, using a new clustering algorithm, indicated that the BMI1 oncogene is predominantly expressed in the subset of non-GC phenotype DLBCL (67). These results collectively show that BMI1 expression in malignant B-cell lymphomas correlates with their biological behavior, suggesting that BMI1 plays a role in development of these malignancies. In addition, BMI1 expression patterns may be diagnostically relevant (55).

An immediate question is whether there is any evidence that BMI1 expression in human malignant lymphomas results in suppression of p16^INK4A/p14^ARF, as it does in mice. In HL and HL-derived cell lines, the presence of BMI1 in tumor cells was not related to absence of p16^INK4a expression: 50% of the HL patients showed strong nuclear co-expression of BMI1 and p16^INK4a (58). Importantly, neoplastic cells that were positive for both BMI1 and p16^INK4a also expressed the proliferation marker MIB1, suggesting that they were in cycle despite the presence of p16^INK4a. More recent unpublished studies of diffuse LBCL also demonstrated that the presence of BMI1 in MIB1^POS neoplastic cells does not necessarily coincide with the absence of p16^INK4a or p14^ARF (van Galen et al., manuscript in preparation). These findings agree with studies of p16^INK4a in aggressive LBCL and HL published by others, which showed that these tumors frequently express p16^INK4a and p14^ARF and that loss of p16^INK4a/P14^ARF is mainly associated with promoter hypermethylation, gene loss or mutation (68). Although the currently available evidence does not allow us to rule out that BMI1, being an epigenetic regulator, contributes to hypermethylation of the p16^INK4a/p14^ARF promoter, the PcG expression studies collectively show that the presence of BMI1 in human malignant LBCL does not clearly correlate with the absence of p16^INK4a. What explains this discrepancy with the mouse studies? A recent screening of human cells using almost 8000 siRNA constructs for different human genes showed that BMI1 was not among the genes that allow circumvention of the p53 pathway (69). Therefore, the target genes of BMI1 in human lymphocytes may be different from those in mouse lymphocytes. An alternative explanation is that the PRC1 complex in human lymphocytes behaves differently than in mouse lymphocytes, for instance, because of distinct variation in mouse and human PcG complex composition. This could lead to altered activity of the PcG complex, because several binding partners of BMI1 have opposing roles (70,71). Also, major players in the Rb–p16 pathway are capable of directly interacting with members of the PRC1 PcG complex, and the amount of BMI1 and HPC2 may determine whether the PcG silencing complex is targeted toward the p16^INK4a/p14^ARF locus or toward cyclin A and cdc2 genes (72).

	PcG ONCOGENE EXPRESSION IN HUMAN EPITHELIAL TUMORS

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Is abnormal PcG gene expression particular for hematological malignancies or is PcG gene expression also disturbed in other human cancers? Our recent work and that of others demonstrated that neoplastic cells in solid tumors, including medulloblastomas (6), and tumors originating from liver (73,74), colon (74), breast (49,75,76), lung (74,77), penis (78) and prostate (79), all display disproportionate expression of PcG genes. Also, some of these patterns are associated with loss of differentiation by tumor cells, metastatic behavior and a worse prognosis.

Similar to GC B-cells, healthy epithelial cells in lung and breast tissue primarily employ PRC1 genes, including BMI1, in the absence of EZH2 (75,80). However, in premalignant precursor lesion of lung carcinomas and bronchial squamous cell carcinomas, increased expression of BMI1 is observed in dividing cells (77,80). At the same time, expression of EZH2 and the proliferation marker MIB1 is elevated in BMI1^POS cells, according to the severity of the histopathological stage (80). These patterns suggest that altered expressions of BMI1 and EZH2 are early events in development of lung carcinoma and that they precede high proliferation rates. Contrary to the situation in HL (58), upregulation of BMI1 in lung carcinomas correlates with downregulation of p16^INK4a in lung carcinomas (77), penile carcinomas (78) and colorectal cancer (81). This could indicate that the mechanism of cell cycle regulation by BMI1 in epithelial cells is different from the mechanism in lymphocytes, which could be related to cell type-specific variation in PcG complex composition and target gene recognition (10,15).

Interestingly, development of breast cancer appears to follow a similar pattern (75). Major differences in PcG gene expression between normal breast tissue and ductal hyperplasia, well-differentiated ductal carcinoma in situ or well-differentiated invasive carcinomas, could not be demonstrated using immunohistochemistry (75). However, poorly differentiated DCIS and invasive carcinomas were found to frequently express EZH2 in combination with proteins constituting the PRC1 complex (75), and BMI1 overexpression was observed in invasive ductal breast carcinoma and axillary lymph node metastases (82). In addition, whereas the majority of BMI-1/EZH2 double-positive cells in poorly differentiated DCIS were resting, poorly differentiated invasive carcinoma displayed an enhanced rate of cell division within BMI-1/EZH2 double-positive neoplastic cells (75). This suggests that deregulated expression of EZH2 appears to be associated with loss of differentiation and development of poorly differentiated breast cancer in humans and that increased EZH2 expression precedes high frequencies of proliferation during breast cancer development. These patterns are in agreement with an earlier study showing that EZH2 protein levels were strongly associated with breast cancer aggressiveness and that overexpression of EZH2 promotes anchorage-independent growth, cell invasion and transformation (49). Interestingly, increased expression of EZH2 has also been observed in two studies of prostate cancers using a combination of gene expression profiling and tissue arrays (79,83) and has been proposed to be a marker for metastatic prostate cancer (79). However, conflicting results have been reported in studies of prostate (84) and ovarian cancers (85), and it has been suggested that enhanced EZH2 expression may be associated with a subset of tumors defined by high proliferation indices (84,86) and not necessarily reflect a direct contribution of EZH2 to carcinogenesis or metastasis.

	CONCLUDING REMARKS

TOP ABSTRACT POLYCOMB GENES, PROTEINS AND... MECHANISTIC ASPECTS OF GENE... PcG GENES AND THE... PcG ONCOGENE EXPRESSION IN... PcG ONCOGENE EXPRESSION IN... CONCLUDING REMARKS REFERENCES

 
Evidence is rapidly increasing that PcG genes are a novel class of oncogenes and anti-oncogenes, which may in future years become central to the development of novel cancer therapies based on epigenetic gene silencing (87,88). Not only are PcG genes such as BMI-1 and EZH2 capable of cellular transformation, but also they are vital for cell survival. To date, abnormal PcG gene expression has been described in most human cancers. Also, the correlation between PcG expression and biological behavior of clinically defined cancer subtypes suggests that these genes play a central role in oncogenesis, and holds a promise for discovery of novel diagnostic markers (55).

Our current knowledge does not allow us to provide a clear explanation for altered PcG expression in human malignancies yet. Some PcG genes are located on chromosomal regions known to be associated with chromosomal abnormalities (89–91) (Table 2), and gene amplifications of BMI1 and EZH2 have been described in MCL (57) and solid tumors (50) and L3MBTL deletions in myeloid leukemia (91). However, it remains to be determined whether PcG overexpression observed in human tumors is directly related to oncogenesis. In fact, one could even argue that inappropriate PcG expression in cancer cells may not be abnormal at all. For instance, in human LBCL, not only the BMI1 PcG gene appears to be expressed abnormally, but also its binding partners RING1 and HPH1 (55). Is it possible that these genes, present on different chromosomes, are coordinately deregulated, in addition to all the other genetic abnormalities that have been described in malignant lymphomas? Or is there an alternative explanation? Recently, a minor follicular B-cell subpopulation was discovered that may represent a transitional stage between proliferating centroblasts and resting centrocytes and that expresses all major components of the two PcG complexes (16). In this regard, this population of cells closely resembles dividing neoplastic cells in nodal LBCL and may represent its normal counterpart (54,55). What could be the relevance of this observation? In Drosophila, coexpression and actual interaction between the two PcG complexes occur only transiently during early larval development (43). At later stages, the two complexes are separated, like they are in the majority of healthy GC B-cells (16,62). Are healthy follicular B-cells, in which PRC1 and PRC2 core components are coexpressed, more susceptible for malignant transformation, because chromatin-modifying enzymatic activities that are normally separated in PRC1 and PRC2 are active at the same time? And does the ‘abnormal PcG expression pattern’ in nodal LBCL then merely reflect a gene expression profile that is frozen at a time of transformation?

Another aspect of PcG gene expression in tumors that we need to understand in more detail is how PcG genes affect the biological behavior of tumor cells. Obviously, inappropriate expression epigenetic regulators may result in loss of normal gene silencing pathways and thus contribute to loss of cell identity. One possibility is that this underlies the observed epigenetic alterations seen in many tumor cells (87,92). A very recent development (reviewed in 93,94) is the finding that BMI1 is vital for survival of healthy and leukemic stem cells. It has been proposed that BMI1 may not only confer a growth advantage to cells, but also confer ‘stemness’ to cells which might place PcG genes central in the process of dedifferentiation (92). In future years, fundamental epigenesis research shall answer many of our questions and direct us to novel biological problems. Polycomb research is clearly leading us to a better understanding of new theories in cancer research, but it will also shine a new and brighter light on classic tumor cell biology.

	REFERENCES

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1. Koga, H., Kaji, Y., Nishii, K., Shirai, M., Tomotsune, D., Osugi, T., Sawada, A., Kim, J.Y., Hara, J., Miwa, T. et al. (2002) Overexpression of Polycomb-group gene rae28 in cardiomyocytes does not complement abnormal cardiac morphogenesis in mice lacking rae28 but causes dilated cardiomyopathy. Lab. Invest., 82, 375–385.[CrossRef][Web of Science][Medline]

2. Caretti, G., Di Padova, M., Micales, B., Lyons, G.E. and Sartorelli, V. (2004) The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev., 18, 2627–2638.[Abstract/Free Full Text]

3. Akasaka, T., Kanno, M., Balling, R., Mieza, M.A., Taniguchi, M. and Koseki, H. (1996) A role for mel-18, a Polycomb group-related vertebrate gene, during the anteroposterior specification of the axial skeleton. Development, 122, 1513–1522.[Abstract]

4. Alkema, M.J., van der Lugt, N.M., Bobeldijk, R.C., Berns, A. and van Lohuizen, M. (1995) Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice. Nature, 374, 724–727.[CrossRef][Medline]

5. del Mar, L.M., Marcos-Gutierrez, C., Perez, C., Schoorlemmer, J., Ramirez, A., Magin, T. and Vidal, M. (2000) Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice. Development, 127, 5093–5100.[Abstract]

6. Leung, C., Lingbeek, M., Shakhova, O., Liu, J., Tanger, E., Saremaslani, P., van Lohuizen, M. and Marino, S. (2004) Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature, 428, 337–341.[CrossRef][Medline]

7. van der Lugt, N.M., Domen, J., Linders, K., van Roon, M., Robanus-Maandag, E., te, R.H., van, D.V., Deschamps, J., Sofroniew, M. and van Lohuizen, M. (1994) Posterior transformation, neurological abnormalities and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev., 8, 757–769.[Abstract/Free Full Text]

8. Heard, E. (2004) Recent advances in X-chromosome inactivation. Curr. Opin. Cell Biol., 16, 247–255.[CrossRef][Web of Science][Medline]

9. Lund, A.H. and van Lohuizen, M. (2004) Polycomb complexes and silencing mechanisms. Curr. Opin. Cell Biol., 16, 239–246.[CrossRef][Web of Science][Medline]

10. Otte, A.P. and Kwaks, T.H. (2003) Gene repression by Polycomb group protein complexes: a distinct complex for every occasion? Curr. Opin. Genet. Dev., 13, 448–454.[CrossRef][Web of Science][Medline]

11. Sewalt, R.G., Kwaks, T.H., Hamer, K. and Otte, A.P. (2004) Biochemical analysis of mammalian polycomb group protein complexes and the identification of genetic elements that block polycomb-mediated gene repression. Methods Enzymol., 377, 282–296.[Web of Science][Medline]

12. Jacobs, J.J. and van Lohuizen, M. (2002) Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim. Biophys. Acta, 1602, 151–161.[Medline]

13. Lessard, J. and Sauvageau, G. (2003) Polycomb group genes as epigenetic regulators of normal and leukemic hemopoiesis. Exp. Hematol., 31, 567–585.[CrossRef][Web of Science][Medline]

14. Attwooll, C., Oddi, S., Cartwright, P., Prosperini, E., Agger, K., Steensgaard, P., Wagener, C., Sardet, C., Moroni, M.C. and Helin, K. (2004) A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. J. Biol. Chem., 280, 1199–1208.

15. Gunster, M.J., Raaphorst, F.M., Hamer, K.M., den Blaauwen, J.L., Fieret, E., Meijer, C.J. and Otte, A.P. (2001) Differential expression of human Polycomb group proteins in various tissues and cell types. J. Cell. Biochem., 81 (Suppl. 36), 129–143.[CrossRef]

16. Van Galen, J.C., Dukers, D.F., Giroth, C., Sewalt, R.G., Otte, A.P., Meijer, C.J. and Raaphorst, F.M. (2004) Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction. Eur. J. Immunol., 34, 1870–1881.[CrossRef][Web of Science][Medline]

17. Akasaka, T., Takahashi, N., Suzuki, M., Koseki, H., Bodmer, R. and Koga, H. (2002) MBLR, a new RING finger protein resembling mammalian Polycomb gene products, is regulated by cell cycle-dependent phosphorylation. Genes Cells, 7, 835–850.[Abstract]

18. Sewalt, R.G., Gunster, M.J., van der Vlag, J., Satijn, D.P. and Otte, A.P. (1999) C-terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol. Cell. Biol., 19, 777–787.[Abstract/Free Full Text]

19. Trimarchi, J.M., Fairchild, B., Wen, J. and Lees, J.A. (2001) The E2F6 transcription factor is a component of the mammalian Bmi1- containing polycomb complex. Proc. Natl Acad. Sci. USA, 98, 1519–1524.[Abstract/Free Full Text]

20. Qin, H., Wang, J., Liang, Y., Taniguchi, Y., Tanigaki, K. and Han, H. (2004) RING1 inhibits transactivation of RBP-J by Notch through interaction with LIM protein KyoT2. Nucleic Acids Res., 32, 1492–1501.[Abstract/Free Full Text]

21. Garcia, E., Marcos-Gutierrez, C., del Mar, L.M., Moreno, J.C. and Vidal, M. (1999) RYBP, a new repressor protein that interacts with components of the mammalian Polycomb complex and with the transcription factor YY1. EMBO J., 18, 3404–3418.[CrossRef][Web of Science][Medline]

22. Garcia-Cuellar, M.P., Zilles, O., Schreiner, S.A., Birke, M., Winkler, T.H. and Slany, R.K. (2001) The ENL moiety of the childhood leukemia-associated MLL-ENL oncoprotein recruits human Polycomb 3. Oncogene, 20, 411–419.[CrossRef][Web of Science][Medline]

23. Soulez, M., Saurin, A.J., Freemont, P.S. and Knight, J.C. (1999) SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co- localize with the human Polycomb group complex. Oncogene, 18, 2739–2746.[CrossRef][Web of Science][Medline]

24. Voncken, J.W., Niessen, H., Neufeld, B., Rennefahrt, U., Dahlmans, V., Kubben, N., Holzer, B., Ludwig, S. and Rapp, U.R. (2004) MAPKAP kinase 3pK phosphorylates and regulates chromatin-association of the polycomb-group protein Bmi1. J. Biol. Chem., 280, 5178–5187.

25. Strahl, B.D. and Allis, C.D. (2000) The language of covalent histone modifications. Nature, 403, 41–45.[CrossRef][Medline]

26. van der Vlag, J. and Otte, A.P. (1999) Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat. Genet., 23, 474–478.[CrossRef][Web of Science][Medline]

27. Cao, R., Wang, L., Wang, H., Xia, L., Erdjument-Bromage, H., Tempst, P., Jones, R.S. and Zhang, Y. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science, 298, 1039–1043.[Abstract/Free Full Text]

28. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. and Reinberg, D. (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Genes Dev., 16, 2893–2905.[Abstract/Free Full Text]

29. Kuzmichev, A., Jenuwein, T., Tempst, P. and Reinberg, D. (2004) Different ezh2-containing complexes target methylation of histone h1 or nucleosomal histone h3. Mol. Cell, 14, 183–193.[CrossRef][Web of Science][Medline]

30. Kagey, M.H., Melhuish, T.A., Powers, S.E. and Wotton, D. (2005) Multiple activities contribute to Pc2 E3 function. EMBO J., 24, 108–119.[CrossRef][Web of Science][Medline]

31. Sewalt, R.G., Lachner, M., Vargas, M., Hamer, K.M., den Blaauwen, J.L., Hendrix, T., Melcher, M., Schweizer, D., Jenuwein, T. and Otte, A.P. (2002) Selective interactions between vertebrate Polycomb homologs and the SUV39H1 histone lysine methyltransferase suggest that histone H3-K9 methylation contributes to chromosomal targeting of Polycomb group proteins. Mol. Cell. Biol., 22, 5539–5553.[Abstract/Free Full Text]

32. Fang, J., Chen, T., Chadwick, B., Li, E. and Zhang, Y. (2004) Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J. Biol. Chem., 279, 52812–52815.[Abstract/Free Full Text]

33. Wang, H., Wang, L., Erdjument-Bromage, H., Vidal, M., Tempst, P., Jones, R.S. and Zhang, Y. (2004) Role of histone H2A ubiquitination in Polycomb silencing. Nature, 431, 873–878.[CrossRef][Web of Science][Medline]

34. de Napoles, M., Mermoud, J.E., Wakao, R., Tang, Y.A., Endoh, M., Appanah, R., Nesterova, T.B., Silva, J., Otte, A.P., Vidal, M., Koseki, H. and Brockdorff, N. (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev.Cell, 7, 663–676.[CrossRef][Web of Science][Medline]

35. Muller, J., Hart, C.M., Francis, N.J., Vargas, M.L., Sengupta, A., Wild, B., Miller, E.L., O'Connor, M.B., Kingston, R.E. and Simon, J.A. (2002) Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell, 111, 197–208.[CrossRef][Web of Science][Medline]

36. Czermin, B., Melfi, R., McCabe, D., Seitz, V., Imhof, A. and Pirrotta, V. (2002) Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell, 111, 185–196.[CrossRef][Web of Science][Medline]

37. Tie, F., Furuyama, T., Prasad-Sinha, J., Jane, E. and Harte, P.J. (2001) The Drosophila Polycomb group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3. Development, 128, 275–286.[Abstract]

38. Furuyama, T., Banerjee, R., Breen, T.R. and Harte, P.J. (2004) SIR2 is required for polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr. Biol., 14, 1812–1821.[CrossRef][Web of Science][Medline]

39. Kirmizis, A., Bartley, S.M., Kuzmichev, A., Margueron, R., Reinberg, D., Green, R. and Farnham, P.J. (2004) Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev., 18, 1592–1605.[Abstract/Free Full Text]

40. Breiling, A., O'Neill, L.P., D'Eliseo, D., Turner, B.M. and Orlando, V. (2004) Epigenome changes in active and inactive polycomb-group-controlled regions. EMBO Rep., 5, 976–982.[CrossRef][Web of Science][Medline]

41. Ringrose, L., Ehret, H. and Paro, R. (2004) Distinct contributions of histone H3 lysine 9 and 27 methylation to locus-specific stability of polycomb complexes. Mol. Cell, 16, 641–653.[CrossRef][Web of Science][Medline]

42. Pasini, D., Bracken, A.P., Jensen, M.R., Denchi, E.L. and Helin, K. (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J., 23, 4061–4071.[CrossRef][Web of Science][Medline]

43. Poux, S., Melfi, R. and Pirrotta, V. (2001) Establishment of Polycomb silencing requires a transient interaction between PC and ESC. Genes Dev., 15, 2509–2514.[Abstract/Free Full Text]

44. Haupt, Y., Bath, M.L., Harris, A.W. and Adams, J.M. (1993) bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene, 8, 3161–3164.[Web of Science][Medline]

45. van Lohuizen, M., Verbeek, S., Scheijen, B., Wientjens, E., van der, G.H. and Berns, A. (1991) Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell, 65, 737–752.[CrossRef][Web of Science][Medline]

46. Haupt, Y., Alexander, W.S., Barri, G., Klinken, S.P. and Adams, J.M. (1991) Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell, 65, 753–763.[CrossRef][Web of Science][Medline]

47. Jacobs, J.J., Scheijen, B., Voncken, J.W., Kieboom, K., Berns, A. and van Lohuizen, M. (1999) Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc- induced apoptosis via INK4a/ARF. Genes Dev., 13, 2678–2690.[Abstract/Free Full Text]

48. Jacobs, J.J., Kieboom, K., Marino, S., DePinho, R.A. and van Lohuizen, M. (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature, 397, 164–168.[CrossRef][Medline]

49. Kleer, C.G., Cao, Q., Varambally, S., Shen, R., Ota, I., Tomlins, S.A., Ghosh, D., Sewalt, R.G., Otte, A.P., Hayes, D.F. et al. (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA, 100, 11606–11611.[Abstract/Free Full Text]

50. Bracken, A.P., Pasini, D., Capra, M., Prosperini, E., Colli, E. and Helin, K. (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J., 22, 5323–5335.[CrossRef][Web of Science][Medline]

51. Tang, X., Milyavsky, M., Shats, I., Erez, N., Goldfinger, N. and Rotter, V. (2004) Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene, 23, 5759–5769.[CrossRef][Web of Science][Medline]

52. Itahana, K., Zou, Y., Itahana, Y., Martinez, J.L., Beausejour, C., Jacobs, J.J., van Lohuizen, M., Band, V., Campisi, J. and Dimri, G.P. (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol., 23, 389–401.[Abstract/Free Full Text]

53. Dimri, G.P., Martinez, J.L., Jacobs, J.J., Keblusek, P., Itahana, K., van Lohuizen, M., Campisi, J., Wazer, D.E. and Band, V. (2002) The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res., 62, 4736–4745.[Abstract/Free Full Text]

54. van Kemenade, F.J., Raaphorst, F.M., Blokzijl, T., Fieret, E., Hamer, K.M., Satijn, D.P., Otte, A.P. and Meijer, C.J. (2001) Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood, 97, 3896–3901.[Abstract/Free Full Text]

55. Raaphorst, F.M., Vermeer, M., Fieret, E., Blokzijl, T., Dukers, D., Sewalt, R.G., Otte, A.P., Willemze, R. and Meijer, C.J. (2004) Site-specific expression of Polycomb-group genes encoding the HPC-HPH/PRC1 complex in clinically defined primary nodal and cutaneous large B-cell lymphomas. Am. J. Pathol., 164, 533–542.[Abstract/Free Full Text]

56. Visser, H.P., Gunster, M.J., Kluin-Nelemans, H.C., Manders, E.M., Raaphorst, F.M., Meijer, C.J., Willemze, R. and Otte, A.P. (2001) The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br. J. Haematol., 112, 950–958.[CrossRef][Web of Science][Medline]

57. Bea, S., Tort, F., Pinyol, M., Puig, X., Hernandez, L., Hernandez, S., Fernandez, P.L., van Lohuizen, M., Colomer, D. and Campo, E. (2001) BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res., 61, 2409–2412.[Abstract/Free Full Text]

58. Dukers, D.F., Van Galen, J.C., Giroth, C., Jansen, P., Sewalt, R.G., Otte, A.P., Kluin-Nelemans, H.C., Meijer, C.J. and Raaphorst, F.M. (2004) Unique Polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines. Am. J. Pathol., 164, 873–881.[Abstract/Free Full Text]

59. Raaphorst, F.M., van Kemenade, F.J., Blokzijl, T., Fieret, E., Hamer, K.M., Satijn, D.P., Otte, A.P. and Meijer, C.J. (2000) Coexpression of BMI-1 and EZH2 polycomb group genes in Reed–Sternberg cells of Hodgkin's disease. Am. J. Pathol., 157, 709–715.[Abstract/Free Full Text]

60. Sanchez-Beato, M., Sanchez, E., Garcia, J.F., Perez-Rosado, A., Montoya, M.C., Fraga, M., Artiga, M.J., Navarrete, M., Abraira, V., Morente, M. et al. (2004) Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors. J. Pathol., 204, 528–537.[CrossRef][Web of Science][Medline]

61. Raaphorst, F.M., Otte, A.P., van Kemenade, F.J., Blokzijl, T., Fieret, E., Hamer, K.M., Satijn, D.P. and Meijer, C.J. (2001) Distinct bmi-1 and ezh2 expression patterns in thymocytes and mature t cells suggest a role for polycomb genes in human t cell differentiation. J. Immunol., 166, 5925–5934.[Abstract/Free Full Text]

62. Raaphorst, F.M., van Kemenade, F.J., Fieret, E., Hamer, K.M., Satijn, D.P., Otte, A.P. and Meijer, C.J. (2000) Cutting edge: polycomb gene expression patterns reflect distinct B cell differentiation stages in human germinal centers. J. Immunol., 164, 1–4.[Abstract/Free Full Text]

63. Grange, F., Bekkenk, M.W., Wechsler, J., Meijer, C.J., Cerroni, L., Bernengo, M., Bosq, J., Hedelin, G., Fink, P.R., van Vloten, W.A. et al. (2001) Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J. Clin. Oncol., 19, 3602–3610.[Abstract/Free Full Text]

64. Rijlaarsdam, J.U., Toonstra, J., Meijer, O.W., Noordijk, E.M. and Willemze, R. (1996) Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J. Clin. Oncol., 14, 549–555.[Abstract/Free Full Text]

65. Pandolfino, T.L., Siegel, R.S., Kuzel, T.M., Rosen, S.T. and Guitart, J. (2000) Primary cutaneous B-cell lymphoma: review and current concepts. J. Clin. Oncol., 18, 2152–2168.[Abstract/Free Full Text]

66. Vermeer, M.H., Geelen, F.A., van Haselen, C.W., Voorst Vader, P.C., Geerts, M.L., van Vloten, W.A. and Willemze, R. (1996) Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch. Dermatol., 132, 1304–1308.[Abstract/Free Full Text]

67. de Boer, W.P., Oudejans, J.J., Meijer, C.J. and Lankelma, J. (2003) Analysing gene expressions with GRANK. Bioinformatics., 19, 2000–2001.[Abstract/Free Full Text]

68. Taniguchi, T., Chikatsu, N., Takahashi, S., Fujita, A., Uchimaru, K., Asano, S., Fujita, T. and Motokura, T. (1999) Expression of p16INK4A and p14ARF in hematological malignancies. Leukemia, 13, 1760–1769.[CrossRef][Web of Science][Medline]

69. Berns, K., Hijmans, E.M., Mullenders, J., Brummelkamp, T.R., Velds, A., Heimerikx, M., Kerkhoven, R.M., Madiredjo, M., Nijkamp, W., Weigelt, B. et al. (2004) A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature, 428, 431–437.[CrossRef][Medline]

70. Satijn, D.P., Olson, D.J., van der Vlag, J., Hamer, K.M., Lambrechts, C., Masselink, H., Gunster, M.J., Sewalt, R.G., van Driel, R. and Otte, A.P. (1997) Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis. Mol. Cell. Biol., 17, 6076–6086.[Abstract]

71. Kanno, M., Hasegawa, M., Ishida, A., Isono, K. and Taniguchi, M. (1995) mel-18, a Polycomb group-related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity. EMBO J., 14, 5672–5678.[Web of Science][Medline]

72. Dahiya, A., Wong, S., Gonzalo, S., Gavin, M. and Dean, D.C. (2001) Linking the rb and polycomb pathways. Mol. Cell, 8, 557–569.[CrossRef][Web of Science][Medline]

73. Neo, S.Y., Leow, C.K., Vega, V.B., Long, P.M., Islam, A.F., Lai, P.B., Liu, E.T. and Ren, E.C. (2004) Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. Hepatology, 39, 944–953.[CrossRef][Web of Science][Medline]

74. Wang, S., Robertson, G.P. and Zhu, J. (2004) A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers. Gene, 343, 69–78.[CrossRef][Web of Science][Medline]

75. Raaphorst, F.M., Meijer, C.J., Fieret, E., Blokzijl, T., Mommers, E., Buerger, H., Packeisen, J., Sewalt, R.A., Otte, A.P. and van Diest, P.J. (2003) Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene. Neoplasia, 5, 481–488.[Web of Science][Medline]

76. Clark, J., Edwards, S., John, M., Flohr, P., Gordon, T., Maillard, K., Giddings, I., Brown, C., Bagherzadeh, A., Campbell, C. et al. (2002) Identification of amplified and expressed genes in breast cancer by comparative hybridization onto microarrays of randomly selected cDNA clones. Genes Chromosomes. Cancer, 34, 104–114.[CrossRef][Web of Science][Medline]

77. Vonlanthen, S., Heighway, J., Altermatt, H.J., Gugger, M., Kappeler, A., Borner, M.M., Lohuizen, M. and Betticher, D.C. (2001) The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br. J. Cancer, 84, 1372–1376.[CrossRef][Web of Science][Medline]

78. Ferreux, E., Lont, A.P., Horenblas, S., Gallee, M.P., Raaphorst, F.M., Von Knebel, D.M., Meijer, C.J. and Snijders, P.J. (2003) Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J. Pathol., 201, 109–118.[CrossRef][Web of Science][Medline]

79. Varambally, S., Dhanasekaran, S.M., Zhou, M., Barrette, T.R., Kumar-Sinha, C., Sanda, M.G., Ghosh, D., Pienta, K.J., Sewalt, R.G., Otte, A.P., Rubin, M.A. and Chinnaiyan, A.M. (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 419, 624–629.[CrossRef][Medline]

80. Breuer, R.H., Snijders, P.J., Smit, E.F., Sutedja, T.G., Sewalt, R.G., Otte, A.P., van Kemenade, F.J., Postmus, P.E., Meijer, C.J. and Raaphorst, F.M. (2005) Increased expression of the EZH2 Polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis. Neoplasia, 6, 736–743.

81. Kim, J.H., Yoon, S.Y., Kim, C.N., Joo, J.H., Moon, S.K., Choe, I.S., Choe, Y.K. and Kim, J.W. (2004) The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett., 203, 217–224.[CrossRef][Web of Science][Medline]

82. Kim, J.H., Yoon, S.Y., Jeong, S.H., Kim, S.Y., Moon, S.K., Joo, J.H., Lee, Y., Choe, I.S. and Kim, J.W. (2004) Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast, 13, 383–388.[CrossRef][Web of Science][Medline]

83. LaTulippe, E., Satagopan, J., Smith, A., Scher, H., Scardino, P., Reuter, V. and Gerald, W.L. (2002) Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res., 62, 4499–4506.[Abstract/Free Full Text]

84. Lapointe, J., Li, C., Higgins, J.P., van de, R.M., Bair, E., Montgomery, K., Ferrari, M., Egevad, L., Rayford, W., Bergerheim, U. et al. (2004) Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA, 101, 811–816.[Abstract/Free Full Text]

85. Adib, T.R., Henderson, S., Perrett, C., Hewitt, D., Bourmpoulia, D., Ledermann, J. and Boshoff, C. (2004) Predicting biomarkers for ovarian cancer using gene-expression microarrays. Br.J.Cancer, 90, 686–692.

86. Sellers, W.R. and Loda, M. (2002) The EZH2 polycomb transcriptional repressor-a marker or mover of metastatic prostate cancer? Cancer Cell, 2, 349–350.[CrossRef][Web of Science][Medline]

87. Nakao, M., Minami, T., Ueda, Y., Sakamoto, Y. and Ichimura, T. (2004) Epigenetic system: a pathway to malignancies and a therapeutic target. Int. J. Hematol., 80, 103–107.[CrossRef][Web of Science][Medline]

88. Egger, G., Liang, G., Aparicio, A. and Jones, P.A. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457–463.[CrossRef][Medline]

89. Katoh, M. and Katoh, M. (2003) Identification and characterization of ASXL2 gene in silico. Int. J. Oncol., 23, 845–850.[Web of Science][Medline]

90. Fisher, C.L., Berger, J., Randazzo, F. and Brock, H.W. (2003) A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11. Gene, 306, 115–126.[CrossRef][Web of Science][Medline]

91. Bench, A.J., Li, J., Huntly, B.J., Delabesse, E., Fourouclas, N., Hunt, A.R., Deloukas, P. and Green, A.R. (2004) Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies. Br. J. Haematol., 127, 509–518.[CrossRef][Web of Science][Medline]

92. Sugimura, T. and Ushijima, T. (2000) Genetic and epigenetic alterations in carcinogenesis. Mutat. Res., 462, 235–246.[CrossRef][Web of Science][Medline]

93. Valk-Lingbeek, M.E., Bruggeman, S.W. and van Lohuizen, M. (2004) Stem cells and cancer; the polycomb connection. Cell, 118, 409–418.[CrossRef][Web of Science][Medline]

94. Raaphorst, F.M. (2003) Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi-1. Trends Immunol., 24, 522–524.[CrossRef][Web of Science][Medline]

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