Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Published OnlineFirst February 10, 2014; DOI: 10.1158/1541-7786.MCR-13-0596

Molecular Cancer Perspective Research

Yukiya Yamamoto, Akihiro Abe, and Nobuhiko Emi

Abstract The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR- like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 1–6. 2014 AACR.

Introduction yses identified BCOR as a complex comprising ring finger fi A major cause of developmental diseases and cancers is the protein 2 (RFN2)/ring nger protein 1B (RING1B), poly- combgroupringfinger1(PCGF1)/nervoussystempolycomb dysregulation of proper transcriptional control, a process that fi is directly regulated by transcription factors, coactivators, and 1 (NSPC1), lysine-speci c demethylase 2B (KDM2B)/ corepressors. Till date, several hundred transcriptional cor- F-box and leucine-rich repeat protein 10 (FBXL10), egulators have been reported in the literature. Recently, the BCOR-like 1 (BCORL1), Ring 1 and YY1 binding protein (RYBP), YY1-associated factor 2 (YAF2), and S phase kinase- increased use of massively parallel sequencing techniques has – expanded our knowledge on the induction of congenital associated protein 1 (SKP1; refs. 2 4). The BCOR complex diseases and cancers caused by specific gene mutations. components are similar to the polycomb repressive complex 1 (PRC1) components (Fig. 1; ref. 5). The BCL6 Corepressor Complex as a Repressive, Transcriptional Machinery The BCOR Complex Is a Distinct Subtype of PRC1 fi The BCL6 corepressor (BCOR) was originally identi ed in In higher eukaryotes, polycomb proteins form chromatin- 2000 as an interacting corepressor of BCL6 (1). This core- modifying complexes that transcriptionally silence genome pressor interacts with histone deacetylases and enhances regions. Two main families of complexes, PRC1 and BCL6-mediated transcriptional repression.Biochemical anal- PRC2, are targeted to repressed, heterochromatic genome regions. Generally, PRC2 methylates histone H3 on lysine 27 (H3K27), whereas canonical PRC1 is recruited to the Authors' Affiliation: Department of Hematology, School of Medicine, genome regions via H3K27me3. Subsequently, PRC1 Fujita Health University, Toyoake, Aichi, Japan monoubiquitylates histone H2A on lysine 119 (H2AK119) Corresponding Authors: Yukiya Yamamoto, Department of Hematology, to induce transcriptional repression. A recent proteomics Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, fi Aichi 470-1192, Japan. Phone: +81-562-939-243; Fax: +81-562-950-016; study led to the classi cation of six groups of PRC1 com- E-mail: [email protected]; Akihiro Abe, [email protected]; and plexes (6). Each of these groups was further categorized as Nobuhiko Emi, [email protected]. either canonical or noncanonical PRC1 complexes. PCGF2/ doi: 10.1158/1541-7786.MCR-13-0596 MEL18 and PCGF4/BMI1 comprise the canonical PRC1 2014 American Association for Cancer Research. complexes, which depend on the presence of a CBX subunit.

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Figure 1. The BCOR complex as a unique repressive, transcriptional machinery at CpG islands within transcription start sites (TSS). Nonmethylated CpG islands are used to recruit KDM2B through its CxxC domain, thus allowing H3K36me2 depletion via the KDM2b jmjC domain in these regions. RING1B monoubiquitylates histone H2A on K119, leading to the inhibition of speciﬁc transcription targets, including Hox, AP-2a, and Ink4b. LRR, leucine-rich region (7); RAWUL, RING ﬁnger- and WD40-associated ubiquitin-like domain (15); PUFD, PCGF Ub-like fold discriminator (15).

Only canonical PRC1 complexes are targeted to OFCD syndrome (MSC-O), gene expression profiling H3K27me3-enriched genome regions through the CBX could not detect any differences between gene expression subunit (6). On the other hand, the BCOR complex is at the Ink4a-arf-ink4b locus in the MSC-O cells and that categorized into a noncanonical PRC1 subgroup called in wild-type MSCs (14). PRC1.1 (6). The BCOR complex includes the core com- PCGF1, another key component of the BCOR components of PRC1, RING1B, and PCGF1 as well as histone plex, is required for efficient H2AK119 monoubiquityla- H3 on lysine 26 (H3K36me) demethylase KDM2B (Fig. 1; tion (Fig. 1). Ross and colleagues observed a strong gain in refs. 2–4, 6). self-renewal and a block in differentiation in lineage- À RING1B is an ubiquitin E3 ligase that catalyzes the marker negative (Lin ) cells that were simultaneously monoubiquitylation of H2AK119, and the binding of depleted of Pcgf1 and Runx1 (11). These data indicated PCGF1 and KDM2B stimulates E3 ligase activity (7, 8). that Pcgf1 primes hematopoietic progenitors for differen- KDM2B recruits the BCOR complex to nonmethylated tiation through H2AK119 monoubiquitylation on HoxA CpG islands (CGI) through the ZF-CxxC DNA-binding cluster genes, thus leading to the inhibition of HoxA domain of KDM2B (Fig. 1), not through H3K27me3- transcription (11). dependent targeting mechanisms (4, 7). In addition, Taken together, these findings indicate that the BCOR ChIP-seq analysis of embryonic stem (ES) cells revealed complex, a distinct subtype of PRC1, epigenetically regu- that KDM2B was enriched near transcription start sites, lates specific gene transcription. including Hox gene loci (7). These data were consistent with fi the ndings that DNA methylation strongly excludes the BCOR recruitment of BCOR complex components (9) and that Germline Mutations in OFCD and Lenz PCGF1 regulates Hox expression (10, 11). Microphthalmia Syndromes Another action of KDM2B is the specific demethylation OFCD syndrome is an X-linked, recessively inherited of H3K36me2 via its jmjC domain (Fig. 1; refs. 8, 12). disease, and affected patients have canine teeth with extreme- However, KDM2B was shown to function as an oncogene ly long roots, congenital cataracts, craniofacial defects, and ink4b by negatively regulating the expression of p15 tumor- cardiac disease. BCOR germline mutations were first reported suppressor gene via H3K36 demethylation in mouse in OFCD syndrome patients in 2004. Ng and colleagues embryonic fibroblasts and Hoxa9/Meis1–induced leuke- reported different frameshift, deletion, and nonsense muta- mia cells (12, 13). In contrast, BCOR was shown to tions in BCOR (located on Xp11.4) in seven OFCD syn- act as a growth suppressor in adult mesenchymal stem drome families (Fig. 2A, lower lane; refs. 16, 17). In addition, cells (MSC) isolated from a patient with oculofaciocar- p.P85L missense mutation in BCOR was identified in 2 diodental (OFCD) syndrome because restoration of wild- patients with Lenz microphthalmia syndrome (16, 17). type BCOR inhibited cell proliferation (14). Although a These finding revealed BCOR as a key transcriptional BCOR mutation significantly increased H3K36me2 regulator during early embryogenesis. This hypothesis has methylation in the MSCs isolated from the patient with been underscored by findings in knockout mouse models of

OF2 Mol Cancer Res; 12(4) April 2014 Molecular Cancer Research

Impact of BCOR and BCORL1 Disruption in Human Cancers

A Figure 2. Schematic representation of the mutations and fusion BCOR proteins involving BCOR and BBD ANK PUFD BCORL1. A, inactivating BCOR mutations. Arrows in the upper lane indicate the positions of somatic mutations identified in cancers and MDS. Arrows in the lower lane indicate the positions of germline mutations identified in OFCD and Lenz microphthalmia B syndromes. Lines in the bottom lane show the deletion ranges in BCORL1 the BCOR locus. B, inactivating CBS ANK BCORL1 mutations. Arrows in the upper lane indicate the position of somatic mutations found in AML, Break point AML-MRC, MDS, and CMML. C, C chromosomal rearrangements BCOR BCORL1 BCOR involving and in BBD ANK PUFD cancers. Black arrows, frameshift mutations; red arrows, nonsense mutations; green arrows, BCOR-RARA missense mutations; and blue BBD ANK DBD LBD arrows, splice-site mutations. BBD, BCL6-binding domain; ANK, BCOR-CCNB3 ankyrin repeat; PUFD, PCGF Ub- BBD ANK PUFD CLD like fold discriminator; CBS, CTBP1-binding site; DBD, DNA- binding domain; LBD, ligand- binding domain; CLD, cyclin-like BCORL1 domain; PRD, proline-rich domain. CBS ANK Break point BCORL1-ELF4 CBS ANK PRD early embryonic development (18). In addition, BCOR bits double dominant-negative activities against the func- regulates adult MSC functions through an epigenetic mech- tions of both RARA and PML. Till date, fewer than 10 anism (14). The transcription factor AP-2a is developmen- fusion partners of RARA have been identified in APL, tally important for the regulation of cell growth, programmed including promyelocytic leukemia zinc finger (PLZF) and cell death, and differentiation. In the MSC-O cells, AP-2a nucleophosmin (NPM). These fusion partners generally was significantly overexpressed consequent to disengagement exert tumor-suppressive functions during leukemogenesis. of BCOR complex repression on the AP-2a promoter (14). The double dominant-negative activity of the PML– Moreover, BCOR mutations led to increased histone RARA fusion protein dysregulates the tumor-suppressive H3K36 methylation in the AP-2a promoter and decreased function of the partner protein; this seems to be one of the histone H2A ubiquitylation (14). causes of leukemogenesis. In fact, NPM is among the most frequently mutated genes in patients with acute myeloid Identification of BCOR-Retinoic Acid Receptor leukemia (AML). Alpha Fusion in a Variant of Acute Promyelocytic Leukemia Somatic BCOR Mutations in a Broad Range of In 2010, our group reported the initial finding of a Human Cancers chimeric BCOR–RARA (retinoic acid receptor alpha) Since 2011, somatic BCOR mutations have been detected transcript in a t(X;17)(p11;q12) acute promyelocytic using whole-exome sequencing in 3.8% unselected patients leukemia (APL) variant (Fig. 2C; ref. 19). Functional with AML with normal karyotypes (CN-AML), 4.2% analysis confirmed that BCOR–RARA inhibited the tran- patients with myelodysplastic syndrome (MDS), and scriptional response to retinoic acid and exhibited aberrant 7.4% patients with chronic myelomonocytic leukemia subcellular localization (19). Typical APL is induced by (CMML; Table 1; refs. 20, 21). In contrast with the negative t(15;17)(q22;q12) translocation, which results in promye- association between NPM1 and BCOR mutations in locytic leukemia (PML)–RARA fusion. PML–RARA exhi- patients with AML, DNA (cytosine-5)-methyltransferase

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Table 1. Frequencies of BCOR and BCORL1 mutations in cancers

Gene Tumor Frequency (%) Clinical outcome Reference # BCOR CN-AML 10/262 (3.8) Unfavorable 20 BCOR MDS 15/354 (4.2) Unfavorable 21 BCOR CMML 4/54 (7.4) N.D. 21 BCOR Retinoblastoma 4/42 (9.5) N.D. 22 BCOR Medulloblastoma 3/92 (3.3) N.D. 23

BCORL1 AML 10/173 (5.8) N.D. 25 BCORL1 MDS 3/354 (0.8) N.D. 21 BCORL1 CMML 1/54 (1.9) N.D. 21 BCORL1 AML-MRC 2/22 (9.1) N.D. 21

Abbreviation: N.D., not determined.

3A (DNMT3A) and runt-related transcription factor 1 similar to those of BCOR mutations (Fig. 2B); however, (RUNX1) mutations were detected in 43.5% and 44.4% the prognostic value of BCORL1 mutations remains unclear. patients with BCOR-mutated AML, respectively (20). Notably, BCORL1 depletion increased the replating capac- À Remarkably, BCOR mutations have been associated with ity of Runx1-depleted Lin cells (11). These results suggest poor prognosis in patients with CN-AML and MDS (20, that BCORL1 dysregulation may be a cause of myeloid 21). In male patients with AML, BCOR mutations disrupted malignancy. the single gene allele, whereas in female patients with AML, the mutations selectively targeted the functional allele BCOR–Cyclin B3 Fusion in a Subtype of Bone BCOR because the exclusive expression of mutated was Sarcoma detected by cDNA-based amplicon deep sequencing (20). Therefore, BCOR may also act as a single-hit tumor-sup- BCOR and BCORL1 are ubiquitously expressed nuclear pressor gene in females. Targeted deep resequencing analyses proteins. It is not surprising that genes belonging to the BCOR of other myeloid-associated mutations revealed that in family are mutated in patients with nonhematologic patients with MDS, somatic BCOR mutations arise after malignancies. Till date, two types of intrachromosomal BCOR mutations in genes involved in splicing machinery or epi- inversions involving the family have been reported. BCOR–CCNB3 fi genetic regulation (21). These somatic mutations were (cyclin B3) fusion was identi ed by RNA- BCOR–CCNB3 scattered throughout the BCOR coding sequence and Seq in a subtype of bone sarcoma (26). fuses BCOR CCNB3 included nonsense, frameshift, insertion/deletion, and con- exons 1 to 15 of to exons 5 to 12 of in an in- CCNB3 sensus splice-site mutations (Fig. 2A, upper lane). However, frame manner (Fig. 2C; ref 26). , located on fi BCOR mutations tended to accumulate on the C-terminal Xp11.22, encodes testis-speci c cyclin B3, a member of the CCNB3 side of the protein, which contains critical domains that highly conserved cyclin family. High expression was BCOR-CCNB3– recruit the main components PCGF1/NSPC1 and KDM2B observed in a positive sarcoma (26); this (2, 15). Finally, frameshift or nonsense mutations in BCOR expression can potentially dysregulate the cell cycle and fi have been also reported in 9.5% patients with retinoblas- induce sarcoma proliferation. Gene expression pro ling BCOR-CCNB3– toma (22) and 3.3% patients with medulloblastoma experiments revealed that this positive sar- (ref. 23; Table 1). coma was biologically distinct from other sarcomas (26).

Somatic BCORL1 Mutations in Myeloid BCORL1–E74-Like Factor 4 Fusion in Malignancies Hepatocellular Carcinoma BCORL1 is a BCOR homolog located on Xq25-q26.1; In addition, BCORL1–ELF4 (E74-like factor 4) fusion this protein acts a transcriptional repressor and contains was identiﬁed in patients with hepatocellular carcinoma. tandem ankyrin repeats and a C-terminal binding protein This in-frame BCORL1–ELF4 fusion combined exons 1 (CtBP)–interacting motif (Fig. 2B; ref. 24). BCORL1 to 11 of BCORL1 with exon 8 of ELF4 (Fig. 2C) and was interacts with class II histone deacetylases and the CtBP generated by an intrachromosomal inversion (27). ELF4/ corepressor through its PXDLS motif (24). Inactivating myeloid elf-1 like factor (MEF) is a transcriptional activator BCORL1 mutations have also been identiﬁed in 5.8% that regulates hematopoietic and glioma stem cell functions patients with AML, 9.1% patients with AML with myelo- as well as several lymphocytes and myelocytes (28, 29). As a dysplasia-related changes (AML-MRC), 0.8% patients with consequence of the chimeric fusion protein, BCORL1– MDS,and 1.9% patients with CMML (Table 1;refs.21,25). ELF4 exhibited decreased repression activity compared with The distribution and types of BCORL1 mutations were BCORL1 (27).

OF4 Mol Cancer Res; 12(4) April 2014 Molecular Cancer Research

Impact of BCOR and BCORL1 Disruption in Human Cancers

BCOR and BCORL1 Are Putative Tumor- proliferation. In addition to germline BCOR mutations in the Suppressor Genes OFCD syndrome, the discovery of somatic mutations and several chimeric fusion transcriptsof BCORand BCORL1 ina We overviewed the genetic mutations that have been broadrangeofhumancancersimplythatBCORandBCORL1 found in the BCOR family in a broad range of human cancers. These findings were previously undetectable are putative tumor-suppressor genes. More importantly, BCOR mutations have been associated with poor prognosis because intrachromosomal rearrangements were difficult to in patients with CN-AML and MDS. Therefore, therapeutic reveal using conventional chromosomal analyses such as interventions in BCOR complex signaling, including G-banding or standard Sanger sequencing. The increased H2AK119 ubiquitylation and H3K36 demethylation, may use of massively parallel sequencing technology to screen improve the prognosis of patients with BCOR complex– large tumor sample series has led to the further identification dysregulated cancers. of novel BCOR family gene mutations. These findings will be valuable for the diagnosis and genetics-based classification of fi Disclosure of Potential Conflicts of Interest unrecognized tumor subtypes, thus providing more bene - fl cial information for estimating patient prognoses and treat- No potential con icts of interest were disclosed. ment responses. The types of BCOR family mutations observed in cancers are generally disruptive to BCOR or Authors' Contributions fi BCOR Conception and design: Y. Yamamoto BCORL1. These ndings support the hypothesis that Acquisition of data (provided animals, acquired and managed patients, provided and BCORL1 are putative tumor-suppressor genes. Howev- facilities, etc.): Y. Yamamoto er, further experiments are needed to prove this hypothesis. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, compu- tational analysis): Y. Yamamoto Writing, review, and/or revision of the manuscript: Y. Yamamoto, A. Abe Conclusions Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Y. Yamamoto The BCOR complex is a noncanonical subtype of the Study supervision: N. Emi PRC1. However, KDM2B recruits the BCOR complex to nonmethylatedCGI,ratherthanactingthroughH3K27me3- Grant Support dependent targeting mechanisms. Furthermore, the BCOR This study was supported by a Grant-in-Aid for Scientific Research from the complex acts as a transcriptional repressor to monoubiquity- Ministry of Education, Culture, Sports, Science, and Technology of Japan to late H2AK119 in specific promoter regions. Currently avail- Y. Yamamoto. able data show that, in contrast with canonical PRC1, the Received November 14, 2013; revised January 28, 2014; accepted January 28, BCORcomplexisnecessaryforpropercell differentiationand 2014; published OnlineFirst February 10, 2014.

References 1. HuynhKD,FischleW,VerdinE,BardwellVJ.BCoR,anovel 10. Wu X, Gong Y, Yue J, Qiang B, Yuan J, Peng X. Cooperation between corepressor involved in BCL-6 repression. Genes Dev 2000;14: EZH2, NSPc1-mediated histone H2A ubiquitination and Dnmt1 in HOX 1810–23. gene silencing. Nucleic Acids Res 2008;36:3590–9. 2. Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ. Polycomb 11. Ross K, Sedello AK, Todd GP, Paszkowski-Rogacz M, Bird AW, Ding L, group and SCF ubiquitin ligases are found in a novel BCOR et al. Polycomb group ring finger 1 cooperates with Runx1 in regulating complex that is recruited to BCL6 targets. Mol Cell Biol 2006; differentiation and self-renewal of hematopoietic cells. Blood 2012; 26:6880–9. 119:4152–61. 3. Sanchez C, Sanchez I, Demmers JA, Rodriguez P, Strouboulis J, 12. He J, Kallin EM, Tsukada Y, Zhang Y. The H3K36 demethylase VidalM.ProteomicsanalysisofRing1B/Rnf2interactorsidentifies a Jhdm1b/Kdm2b regulates cell proliferation and senescence through novel complex with the Fbxl10/Jhdm1B histone demethylase and p15(Ink4b). Nat Struct Mol Biol 2008;15:1169–75. the Bcl6 interacting corepressor. Mol Cell Proteomics 2007;6: 13. He J, Nguyen AT, Zhang Y. KDM2b/JHDM1b, an H3K36me2-specific 820–34. demethylase, is required for initiation and maintenance of acute 4. Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose myeloid leukemia. Blood 2011;117:3869–80. NR, et al. KDM2B links the Polycomb Repressive Complex 1 (PRC1) to 14. Fan Z, Yamaza T, Lee JS, Yu J, Wang S, Fan G, et al. BCOR regulates recognition of CpG islands. Elife 2012;1:e00205. mesenchymal stem cell function by epigenetic mechanisms. Nat Cell 5. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: Biol 2009;11:1002–9. knowns and unknowns. Nature Rev 2009;10:697–708. 15. Junco SE, Wang R, Gaipa JC, Taylor AB, Schirf V, Gearhart MD, et al. 6. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, et al. PCGF Structure of the polycomb group protein PCGF1 in complex with homologs, CBX proteins, and RYBP define functionally distinct PRC1 BCOR reveals basis for binding selectivity of PCGF homologs. Struc- family complexes. Mol Cell 2012;45:344–56. ture 2013;21:665–71. 7. Wu X, Johansen JV, Helin K. Fbxl10/Kdm2b recruits polycomb repres- 16. Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, sive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol et al. Oculofaciocardiodental and Lenz microphthalmia syndromes Cell 2013;49:1134–46. result from distinct classes of mutations in BCOR. Nat Genet 8. Lagarou A, Mohd-Sarip A, Moshkin YM, Chalkley GE, Bezstarosti K, 2004;36:411–6. Demmers JA, et al. dKDM2 couples histone H2A ubiquitylation to 17. Hilton E, Johnston J, Whalen S, Okamoto N, Hatsukawa Y, Nishio J, histone H3 demethylation during Polycomb group silencing. Genes et al. BCOR analysis in patients with OFCD and Lenz microphthalmia Dev 2008;22:2799–810. syndromes, mental retardation with ocular anomalies, and cardiac 9. Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides laterality defects. Eur J Hum Genet 2009;17:1325–35. T. Nucleosome-interacting proteins regulated by DNA and histone 18. Wamstad JA, Corcoran CM, Keating AM, Bardwell VJ. Role of methylation. Cell 2010;143:470–84. the transcriptional corepressor Bcor in embryonic stem cell

www.aacrjournals.org Mol Cancer Res; 12(4) April 2014 OF5

Yamamoto et al.

differentiation and early embryonic development. PLoS ONE 24. Pagan JK, Arnold J, Hanchard KJ, Kumar R, Bruno T, Jones MJ, et al. A 2008;3:e2814. novel corepressor, BCoR-L1, represses transcription through an inter- 19. Yamamoto Y, Tsuzuki S, Tsuzuki M, Handa K, Inaguma Y, Emi N. action with CtBP. J Biol Chem 2007;282:15248–57. BCOR as a novel fusion partner of retinoic acid receptor alpha in a 25. Li M, Collins R, Jiao Y, Ouillette P, Bixby D, Erba H, et al. Somatic t(X;17)(p11;q12) variant of acute promyelocytic leukemia. Blood mutations in the transcriptional corepressor gene BCORL1 in adult 2010;116:4274–83. acute myelogenous leukemia. Blood 2011;118:5914–7. 20. Grossmann V, Tiacci E, Holmes AB, Kohlmann A, Martelli MP, Kern W, 26. Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S, Cohen-Gogo S, et al. Whole-exome sequencing identifies mutations of BCOR in acute et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene myeloid leukemia with normal karyotype. Blood 2011;118:6153–63. fusion. Nat Genet 2012;44:461–6. 21. Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, et al. 27. Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and High-resolution characterization of a hepatocellular carcinoma related disorders. Blood 2013;122:3169–77. genome. Nat Genet 2011;43:464–9. 22. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, 28. Lacorazza HD, Yamada T, Liu Y, Miyata Y, Sivina M, Nunes J, et al. The et al. A novel retinoblastoma therapy from genomic and epigenetic transcription factor MEF/ELF4 regulates the quiescence of primitive analyses. Nature 2012;481:329–34. hematopoietic cells. Cancer Cell 2006;9:175–87. 23. Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair 29. Bazzoli E, Pulvirenti T, Oberstadt MC, Perna F, Wee B, Schultz N, et al. D, Bochicchio J, et al. Medulloblastoma exome sequencing uncovers MEF promotes stemness in the pathogenesis of gliomas. Cell Stem subtype-specific somatic mutations. Nature 2012;488:106–10. Cell 2012;11:836–44.

OF6 Mol Cancer Res; 12(4) April 2014 Molecular Cancer Research

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Yukiya Yamamoto, Akihiro Abe and Nobuhiko Emi

Mol Cancer Res Published OnlineFirst February 10, 2014.

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