Aberration in DNA Methylation in B-Cell Lymphomas Has a Complex Origin and Increases with Disease Severity

English version České info

Despite mounting evidence that epigenetic abnormalities play a key role in cancer biology, their contributions to the malignant phenotype remain poorly understood. Here we studied genome-wide DNA methylation in normal B-cell populations and subtypes of B-cell non-Hodgkin lymphoma: follicular lymphoma and diffuse large B-cell lymphomas. These lymphomas display striking and progressive intra-tumor heterogeneity and also inter-patient heterogeneity in their cytosine methylation patterns. Epigenetic heterogeneity is initiated in normal germinal center B-cells, increases markedly with disease aggressiveness, and is associated with unfavorable clinical outcome. Moreover, patterns of abnormal methylation vary depending upon chromosomal regions, gene density and the status of neighboring genes. DNA methylation abnormalities arise via two distinct processes: i) lymphomagenic transcriptional regulators perturb promoter DNA methylation in a target gene-specific manner, and ii) aberrant epigenetic states tend to spread to neighboring promoters in the absence of CTCF insulator binding sites.

Vyšlo v časopise: Aberration in DNA Methylation in B-Cell Lymphomas Has a Complex Origin and Increases with Disease Severity. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003137
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003137

Souhrn

Zdroje

1. TNHLCP (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89: 3909–3918.

2. TanD, HorningSJ (2008) Follicular lymphoma: clinical features and treatment. Hematol Oncol Clin North Am 22: 863–882, viii.

3. RosenwaldA, WrightG, ChanWC, ConnorsJM, CampoE, et al. (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346: 1937–1947.

4. KleinU, Dalla-FaveraR (2008) Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 8: 22–33.

5. ShaknovichR, CerchiettiL, TsikitasL, KormakssonM, DeS, et al. (2011) DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood 118: 3559–3569.

6. ShaknovichR, GengH, JohnsonNA, TsikitasL, CerchiettiL, et al. (2010) DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood 116: e81–89.

7. ShaknovichR, FigueroaME, MelnickA (2010) HELP (HpaII tiny fragment enrichment by ligation-mediated PCR) assay for DNA methylation profiling of primary normal and malignant B lymphocytes. Methods Mol Biol 632: 191–201.

8. FigueroaME, SkrabanekL, LiY, JiemjitA, FandyTE, et al. (2009) MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 114: 3448–3458.

9. KhulanB, ThompsonRF, YeK, FazzariMJ, SuzukiM, et al. (2006) Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res 16: 1046–1055.

10. ShaknovichR, CerchiettiL, TsikitasL, KormakssonM, DeS, et al. (2011) DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood

11. HansenKD, TimpW, BravoHC, SabunciyanS, LangmeadB, et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43: 768–775.

12. RiesterM, Stephan-Otto AttoliniC, DowneyRJ, SingerS, MichorF (2010) A differentiation-based phylogeny of cancer subtypes. PLoS Comput Biol 6: e1000777 doi:10.1371/journal.pcbi.1000777.

13. TIN-HLPFP (1993) A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. New England Journal of Medicine 329: 987–994.

14. UnoH, CaiT, PencinaMJ, D'AgostinoRB, WeiLJ (2011) On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Statistics in Medicine 30: 1105–1116.

15. TurkerMS (2002) Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene 21: 5388–5393.

16. AhmedI, SarazinA, BowlerC, ColotV, QuesnevilleH (2011) Genome-wide evidence for local DNA methylation spreading from small RNA-targeted sequences in Arabidopsis. Nucleic Acids Res 39: 6919–6931.

17. HathawayNA, BellO, HodgesC, MillerEL, NeelDS, et al. (2012) Dynamics and memory of heterochromatin in living cells. Cell 149: 1447–1460.

18. CuddapahS, JothiR, SchonesDE, RohTY, CuiK, et al. (2009) Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res 19: 24–32.

19. KimTH, AbdullaevZK, SmithAD, ChingKA, LoukinovDI, et al. (2007) Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128: 1231–1245.

20. CiW, PoloJM, CerchiettiL, ShaknovichR, WangL, et al. (2009) The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 113: 5536–5548.

21. VelichutinaI, ShaknovichR, GengH, JohnsonNA, GascoyneRD, et al. (2010) EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116: 5247–5255.

22. YamaneA, ReschW, KuoN, KuchenS, LiZ, et al. (2011) Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol 12: 62–69.

23. SkinniderBF, HorsmanDE, DupuisB, GascoyneRD (1999) Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. Hum Pathol 30: 803–808.

24. CattorettiG, PasqualucciL, BallonG, TamW, NandulaSV, et al. (2005) Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7: 445–455.

25. van GalenJC, DukersDF, GirothC, SewaltRG, OtteAP, et al. (2004) Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction. Eur J Immunol 34: 1870–1881.

26. MorinRD, JohnsonNA, SeversonTM, MungallAJ, AnJ, et al. (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42: 181–185.

27. SuzukiJ, CaputoGR, KondoC, HigginsCB (1990) Cine MR imaging of valvular heart disease: display and imaging parameters affect the size of the signal void caused by valvular regurgitation. AJR Am J Roentgenol 155: 723–727.

28. RimszaLM, LeblancML, UngerJM, MillerTP, GroganTM, et al. (2008) Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP. Blood 112: 3425–3433.

29. XuZ, PoneEJ, Al-QahtaniA, ParkSR, ZanH, et al. (2007) Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination. Crit Rev Immunol 27: 367–397.

30. GuoJU, SuY, ZhongC, MingGL, SongH (2011) Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain. Cell 145: 423–434.

31. BhutaniN, BradyJJ, DamianM, SaccoA, CorbelSY, et al. (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463: 1042–1047.

32. WeisenbergerDJ, VelicescuM, ChengJC, GonzalesFA, LiangG, et al. (2004) Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res 2: 62–72.

33. AngrandPO, ApiouF, StewartAF, DutrillauxB, LossonR, et al. (2001) NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74: 79–88.

34. MorishitaM, di LuccioE (2011) Cancers and the NSD family of histone lysine methyltransferases. Biochim Biophys Acta 1816: 158–163.

35. KangD, ChoHS, ToyokawaG, KogureM, YamaneY, et al. (2012) The histone methyltransferase Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) is involved in human carcinogenesis. Genes Chromosomes Cancer

36. AttiaM, RachezC, De PauwA, AvnerP, RognerUC (2007) Nap1l2 promotes histone acetylation activity during neuronal differentiation. Mol Cell Biol 27: 6093–6102.

37. LeungGP, LeeL, SchmidtTI, ShirahigeK, KoborMS (2011) Rtt107 is required for recruitment of the SMC5/6 complex to DNA double strand breaks. J Biol Chem 286: 26250–26257.

38. RoyMA, D'AmoursD (2011) DNA-binding properties of Smc6, a core component of the Smc5-6 DNA repair complex. Biochem Biophys Res Commun 416: 80–85.

39. LaiAY, FatemiM, DhasarathyA, MaloneC, SobolSE, et al. (2010) DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med 207: 1939–1950.

40. ThompsonRF, ReimersM, KhulanB, GissotM, RichmondTA, et al. (2008) An analytical pipeline for genomic representations used for cytosine methylation studies. Bioinformatics 24: 1161–1167.

41. FujitaPA, RheadB, ZweigAS, HinrichsAS, KarolchikD, et al. (2011) The UCSC Genome Browser database: update 2011. Nucleic Acids Res 39: D876–882.

42. FlicekP, AmodeMR, BarrellD, BealK, BrentS, et al. (2011) Ensembl 2011. Nucleic Acids Res 39: D800–806.

43. OberleyMJ, TsaoJ, YauP, FarnhamPJ (2004) High-throughput screening of chromatin immunoprecipitates using CpG-island microarrays. Methods Enzymol 376: 315–334.

44. MukhopadhyayR, YuW, WhiteheadJ, XuJ, LezcanoM, et al. (2004) The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res 14: 1594–1602.