A Clear Link Between Endogenous Retroviral LTR Activity and Hodgkin's Lymphoma

A clear link between endogenous retroviral LTR activity and Hodgkin’s lymphoma

Katryn J Stacey1, Vitaliya Sagulenko1

1The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld 4072, Australia Cell Research (2010) 20:869-871. doi:10.1038/cr.2010.96; published online 6 July 2010

Abnormal activity of an endogenous invading DNA elements present a risk phoma was demonstrated using soluble retroviral promoter plays a critical for the organism, and the majority are decoy CSF1R which reduced prolifera- role in the development of Hodgkin’s silenced by methylation [5]. tion by approximately 60%, and CSF1R lymphoma, according to a paper in The inappropriate activation of inhibitors which strongly reduced vi- the May issue of Nature Medicine [1]. endogenous retroviruses has been ob- ability of Hodgkin’s lymphoma cells. Throughout evolution, infection of ger- served in a number of different cancers, Caution is needed in interpretation of mline cells with retroviruses has led to although evidence of a direct causal role inhibitor studies, since the inhibitor used the progressive accumulation of endog- in tumour progression has been lacking may also affect related tyrosine kinase enous retroviral elements in genomes. [6]. However, the study by Lamprecht receptors such as KIT and PDGFR [7]. The infecting retroviral RNA is reverse and colleagues [1] clearly shows the However, such inhibitors are promising transcribed into DNA which inserts into role of an endogenous retroviral LTR in for treatment of Hodgkin’s lymphoma. the genome and is then transmitted to development of Hodgkin’s lymphoma. Activation of THE1 LTRs in Hodg- off-spring in a Mendelian manner. There Hodgkin’s lymphoma cells originate kin’s lymphoma cells was not restricted are approximately 443 000 endogenous from mature B cells, but were demon- to the CSF1R locus, but was widespread, retroviral loci in the human genome, strated to require autocrine signaling by indicating a general loss of repression comprising 8% of the total DNA [2]. the macrophage growth factor, colony of these elements. The LTR promoter Most of these contain multiple muta- stimulating factor 1 (CSF1) for prolif- activity was strongly dependent on tions rendering them non-infectious, eration and survival [1]. The receptor for binding sites for NF-κB, AP-1 and Sp1 and there are many instances of isolated CSF1 (CSF1R), a proto-oncogene prod- transcription factors. These sites were long terminal repeat (LTR) viral pro- uct, is normally expressed in cells of the conserved among THE1 subfamily moter elements rather than complete macrophage, osteoclast and trophoblast LTRs, and the constitutive NF-κB and pro-viral sequences. These invading lineages. The lineage-inappropriate AP1 activity found in Hodgkin’s lym- sequences have provided raw materials transcription of the CSF1R (c-fms) gene phoma cells [8] is no doubt important in for the evolution of genomes. A promi- in Hodgkin’s lymphoma cells was not driving the observed promoter activity. nent example of this is the expression initiated from the canonical macrophage The normal widespread suppression of an endogenous retroviral-derived CSF1R promoter but from an LTR of LTR activity by methylation [5] env gene product, syncytin, which is element of the “mammalian apparent pointed to a loss of epigenetic control required for the fusion of trophoblasts LTR retrotransposon” (MaLR) THE1B in Hodgkin’s lymphoma cells. The au- to form a syncytium in the placenta [3]. family, located 6.2 kb upstream (Figure thors identified two CpG elements in More frequently, inserted LTRs provide 1). This aberrant LTR-driven CSF1R the LTR sequence which were strongly alternative promoters, enhancers, splice transcript was detected in lymph nodes demethylated in Hodgkin’s lymphoma sites, poly A signals, or drive antisense from all tested Hodgkin’s lymphoma pa- cells. In contrast, these were at least regulatory transcripts [4]. However, tients and several samples of anaplastic partially methylated in many other lym- large cell lymphoma, but not in primary phoma and leukemia cells, and almost samples of other types of lymphoma. fully methylated in peripheral blood Correspondence: Katryn J Stacey The essential role for CSF1/CSF1R cells of healthy donors. In support of E-mail: [email protected] autocrine signaling in Hodgkin’s lym- perturbed epigenetic modifications npg 870

Normal B cell Hodgkin’s lymphoma cell

NF-κB CSF1 NF-κB CBFA2T3 NF-κB

Me Me NF-κB

P THE1B LTR THE1B LTR CSF1R CSF1R PCSF1R CSF1R

CBFA2T3 CSF1 autocrine loop - survival, proliferation CSF1R

Figure 1 Derepression of an LTR sequence 6.2 kb upstream of the normal macrophage promoter (PCSF1R) is responsible for expression of the CSF1R gene in Hodgkin’s lymphoma cells. In normal B cells, the LTR is CpG methylated (Me) and inactive. Hodgkin’s lymphoma cells have constitutive NF-κB transcription factor activity and loss of transcriptional repressor CBFA2T3, which leads to LTR promoter activity. The normal role of CBFA2T3 in suppressing LTR activity may be indirect. CSF1R expression allows autocrine proliferative and survival signals in Hodgkin’s lymphoma.

being responsible for LTR activation, LTR promoter activity, suggesting that where CSF1R contributes to cancer cell treatment with 5-aza-deoxycytidine to CBFA2T3 alone could not reverse the growth and survival. reduce CpG methylation levels and a chromatin modeling at the active LTR. histone deacetylase inhibitor induced Taken together, the data suggests that References LTR-dependent CSF1R expression activation of THE1 LTRs in Hodgkin’s 1 Lamprecht B, Walter K, Kreher S, et in cells that did not normally express lymphoma depends on both constitutive al. Derepression of an endogenous long CSF1R. NF-κB and epigenetic or mutational terminal repeat activates the CSF1R Mechanisms involved in the loss of silencing of CBFA2T3. The precise proto-oncogene in human lymphoma. epigenetic control of THE1 LTRs in role of CBFA2T3 in suppression of the Nat Med 2010; 16:571-579. Hodgkin’s lymphoma are not clearly THE1 LTRs remains to be established. 2 Lander ES, Linton LM, Birren B, et al. understood, but are likely to involve There are several important im- Initial sequencing and analysis of the CBFA2T3, a transcriptional repressor plications of this work. Whilst many human genome. Nature 2001; 409:860- 921. of the ETO family which normally acts different epigenetic changes have been 3 Mi S, Lee X, Li X, et al. Syncytin via interaction with histone deacetylases implicated in cancer, this is the first is a captive retroviral envelope and co-repressor factors. The authors demonstration of demethylation of an protein involved in human placental found CBFA2T3 was constitutively endogenous retroviral LTR allowing morphogenesis. Nature 2000; 403:785- expressed in normal B cells and non- expression of a proto-oncogene. This 789. Hodgkin’s lymphomas but was strongly nicely illustrates the importance of cel- 4 Gogvadze E, Buzdin A. Retroelements downregulated in Hodgkin’s lymphoma lular mechanisms designed to silence and their impact on genome evolution cells. RNAi-mediated suppression of invading DNA elements. There may and functioning. Cell Mol Life Sci 2009; 66:3727-3742. CBFA2T3 together with induction of well be more examples of LTR-driven 5 Maksakova IA, Mager DL, Reiss D. chronic NF-κB activity were able to genes contributing to cancer. Secondly, Keeping active endogenous retroviral- induce the aberrant LTR-driven CSF1R CSF1R expression has been detected like elements in check: the epigenetic transcript in a leukemic cell line. The in a range of tumors of epithelial ori- perspective. Cell Mol Life Sci 2008; cell line used normally has a high gin (see references in [9]), and it will 65:3329-3347. level of CpG methylation of the THE1 be interesting to determine if there is 6 Ruprecht K, Mayer J, Sauter M, Roemer LTR, but no analysis of methylation similar loss of epigenetic control of K, Mueller-Lantzsch N. Endogenous retroviruses and cancer. Cell Mol Life status following this treatment was pre- the THE1 LTR in any of these cancers. Sci 2008; 65:3366-3382. sented. The authors note that enforced Lastly, CSF-1R signaling is a promis- 7 Irvine KM, Burns CJ, Wilks AF, et expression of CBFA2T3 in Hodgkin’s ing therapeutic target in Hodgkin’s al. A CSF-1 receptor kinase inhibitor lymphoma cells was not able to inhibit lymphoma and any other malignancy targets effector functions and inhibits

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