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Role of the Chromobox Protein CBX7 in Lymphomagenesis

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Role of the Chromobox Protein CBX7 in Lymphomagenesis Role of the chromobox protein CBX7 in lymphomagenesis Clare L. Scott*†,Je´ sus Gil*‡§, Eva Hernando¶, Julie Teruya-Feldstein¶, Masako Narita*, Dolores Martı´nez§, Tapio Visakorpiʈ, David Mu*, Carlos Cordon-Cardo¶, Gordon Peters§, David Beach**, and Scott W. Lowe*††‡‡ *Cold Spring Harbor Laboratory and ††Howard Hughes Medical Institute, Cold Spring Harbor, NY 11724; †Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia; ‡Medical Research Council Clinical Sciences Centre, London W12 ONN, United Kingdom; §Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom; ¶Memorial Sloan–Kettering Cancer Center, New York, NY 10021; ʈUniversity of Tampere and Tampere University Hospital, Tampere 33520, Finland; and **Institute of Cell and Molecular Science, London SE16 4TL, United Kingdom Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved January 26, 2007 (received for review October 4, 2006) Chromobox 7 (CBX7) is a chromobox family protein and a compo- and SUZ12 are also associated with tumorigenesis (7), but none nent of the Polycomb repressive complex 1 (PRC1) that extends the of these has been validated as oncogenes in vivo. lifespan of cultured epithelial cells and can act independently of The Pc homolog Chromobox 7 (CBX7) was identified by BMI-1 to repress the INK4a/ARF tumor suppressor locus. To deter- virtue of its ability to extend the lifespan of primary human mine whether CBX7 might be oncogenic, we examined its expres- prostate epithelial cells (16). CBX7 shares no homology with sion pattern in a range of normal human tissues and tumor BMI-1 but belongs to a mammalian family of chromobox- samples. CBX7 was expressed at high levels in germinal center containing proteins that comprises three homologs of HP1 and lymphocytes and germinal center-derived follicular lymphomas, five homologs of Pc. Although CBX7 can also repress the where elevated expression correlated with high c-Myc expression INK4a/ARF locus, it can function independently of BMI-1 (16). and a more advanced tumor grade. By targeting Cbx7 expression Here, we demonstrate that CBX7 is up-regulated in follicular to the lymphoid compartment in mice, we showed that Cbx7 can lymphoma and possesses oncogenic properties in the hemato- initiate T cell lymphomagenesis and cooperate with c-Myc to poietic compartment, thus identifying CBX7 as a potential produce highly aggressive B cell lymphomas. Furthermore, Cbx7 human oncogene. repressed transcription from the Ink4a/Arf locus and acted epistati- cally to the Arf-p53 pathway during tumorigenesis. These data Results identify CBX7 as a chromobox protein causally linked to cancer Elevated Expression of CBX7 in Human Follicular Lymphoma. To development and may help explain the low frequency of INK4a/ explore the involvement of CBX7 in human cancer, we examined ARF mutations observed in human follicular lymphoma. its expression in the ONCOMINE database (17). Analyzing data from a multicancer study (18), we noted that CBX7 was ex- Ink4a-ARF ͉ oncogene ͉ Polycomb ͉ follicular lymphoma ͉ p53 pressed at significantly higher levels in follicular lymphoma relative to normal germinal center cells, from which follicular lymphoma arises (P ϭ 3.8 ϫ 10Ϫ5). The association between olycomb (Pc) group (PcG) proteins are a class of epigenetic CBX7 expression and follicular lymphoma (Q ϭ 5.3 ϫ 10Ϫ3) was regulators that, despite being structurally unrelated, can be P even more significant than for BCL-2 expression (Q ϭ 1.6 ϫ grouped functionally into two major multiprotein complexes Ϫ 10 2), a striking result given that t(14; 18) translocations involv- referred to as Pc repressive complex 1 and 2 (PRC1 and PRC2). ing BCL-2 are a hallmark of this disease, and Ͼ90% of indolent The PRC2 complex has histone deacetylase and histone methyl follicular lymphomas express high levels of BCL-2 (19). In transferase activities (specific for K27 of histone H3) and accordance with previous reports (11), we did not observe an establishes histone repressive marks on the chromatin (1). These association between BMI-1 expression and follicular lymphoma marks are subsequently read by PRC1 complexes that alter (Fig. 1A). Furthermore, no other PcG gene analyzed was sig- higher chromatin organization, ultimately leading to transcrip- nificantly increased in this data set [supporting information (SI) tional repression (2, 3). Although the precise composition of Table 1]. these two complexes may vary according to cellular context (4), To extend these observations, we analyzed CBX7 levels by the core components of the mammalian PRC1 complex are the immunohistochemistry (IHC) using tissue microarrays that con- homologs of Drosophila Pc, Posterior sex combs, Sex combs tained 168 cases of follicular lymphoma. To this end, we used a extra, and Polyhomeiotic. The PRC2 complex consists of En- previously described polyclonal antibody specific for CBX7 (16) hancer of Zeste (EZH2), Early Embryonic-Deficient (EED), and validated for IHC (20) (see also SI Fig. 5 for further Suppressor of Zeste (SUZ12), and other associated proteins. analyses). A subset of samples (54%) displayed strong or mod- PcG proteins regulate morphogenesis, chromosome X-inacti- vation, hematopoiesis, stem-cell self renewal, and cellular pro- liferation (reviewed in refs. 5 and 6). In addition, several PcG Author contributions: C.L.S. and J.G. contributed equally to this work; C.L.S., J.G., C.C.-C., proteins have been linked to tumorigenesis (7, 8). BMI-1, one of D.B., and S.L. designed research; C.L.S., J.G., E.H., J.T.-F., M.N., D. Martı´nez, and D. Mu performed research; J.T.-F., T.V., and G.P. contributed new reagents/analytic tools; E.H., D. the six mammalian orthologs of Drosophila Psc, is the PcG gene Martı´nez,T.V., D. Mu, and C.C.-C. analyzed data; and C.L.S., J.G., and S.L. wrote the paper. most strongly associated with cancer and was initially identified The authors declare no conflict of interest. for its ability to cooperate with c-Myc in lymphomagenesis (9, This article is a PNAS Direct Submission. 10). Furthermore, BMI-1 is overexpressed in mantle cell lym- Freely available online through the PNAS open access option. phoma and several other malignancies (11). Bmi-1 can extend Abbreviations: Pc, Polycomb; PcG, Pc group; PRC, Pc repressive complex, CBX7, Chromobox proliferative lifespan, reduce apoptosis, and promote transfor- 7; MSCV, murine stem cell virus; HSC, hematopoietic stem cells; IHC, immunohistochemistry; mation of cultured cells and tumorigenesis in mice (12–14). IRES, internal ribosomal entry site. These properties depend on its ability to repress transcription ‡‡To whom correspondence should be addressed. E-mail: [email protected]. from the Ink4a/Arf tumor suppressor locus (13), which controls This article contains supporting information online at www.pnas.org/cgi/content/full/ cellular senescence and apoptosis through regulating the Rb and 0608721104/DC1. CELL BIOLOGY p53 tumor suppressors (15). Other PcG proteins such as EZH2 © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608721104 PNAS ͉ March 27, 2007 ͉ vol. 104 ͉ no. 13 ͉ 5389–5394 Downloaded by guest on September 24, 2021 A CBX7 BCL2 BMI1 100 n=31 2.0 2.0 1.0 B P=3.8 x 10-5 P=2.7 x 10-4 P=0.854 1.5 1.5 0.5 80 1.0 1.0 0.0 60 0.5 0.5 -0.5 n=61 0.0 0.0 -1.0 40 -0.5 -0.5 -1.5 Percentage Expression units 20 Germinal Follicular Germinal Follicular Germinal Follicular n=76 Center Lymphoma Center Lymphoma Center Lymphoma 0 C Grade 2 FL D CBX7 MZ DZ LZ <10% 10-30% 30-50% Grade 1 Grade 2 Grade 3 Low magnification 10-30% <10% 30-50% High magnification Fig. 1. Aberrant expression of CBX7 in human follicular lymphomas. (A) Expression of CBX7, BCL-2, and BMI-1 in germinal center (GC, green) and follicular lymphoma (FL, red), as reported in ref. 18. (B) FL samples were stained by IHC by using anti-CBX7 antibodies and the CBX7 levels evaluated and quantified as explained in Materials and Methods.(C) Representative pictures of FL samples stained with CBX7 antibodies are shown. (D) CBX7 expression in secondary GC of the tonsil. Arrows indicate high CBX7 expression in germinal center histiocytes. erate levels of CBX7 staining (Fig. 1 B and C). Using Fisher’s normal tonsils. Consistent with previous reports (5), BMI-1 was exact test, a statistically significant correlation was observed expressed predominantly in mantle zone (MZ) lymphocytes and between CBX7 expression and Ki67 (P ϭ 0.015) and between to a lesser extent in centrocytes and scattered centroblasts in the CBX7 expression and higher-grade follicular lymphoma (P ϭ dark zone (DZ) and the light zone within the germinal center (SI 0.0004) (SI Table 2). Consistent with the microarray data, a Fig. 7). In contrast, CBX7 was rarely expressed in MZ lympho- subset of lymphomas with high CBX7 levels displayed overex- cytes but accumulated in the germinal center with high expres- pression of CBX7 transcripts as assessed by quantitative RT- sion in histiocytes and lower expression in centrocytes and PCR analysis of paraffin shavings. These same samples showed scattered centroblasts, most predominantly in the DZ (Fig. 1D). no evidence of increased copy number of the CBX7 gene or Although the CBX7 levels observed in CBX7-positive follicular translocation at the CBX7 locus (22q13), suggesting that high lymphomas were higher than in normal germinal center cells, CBX7 levels arise at least in part from increased transcription or from expression data alone, it is difficult to judge whether CBX7 mRNA stability (SI Fig. 6 and data not shown). contributes directly to tumorigenesis or represents a marker of Elevated CBX7 expression also correlated with the presence the cell of origin of this malignancy.
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