Decitabine Induces Gene Derepression on Monosomic Chromosomes:
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 02 2021
15 02 2021
Historique:
received:
28
04
2020
revised:
21
08
2020
accepted:
12
11
2020
pubmed:
19
11
2020
medline:
28
4
2021
entrez:
18
11
2020
Statut:
ppublish
Résumé
Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3-1, with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3-1 and RIG-I mRNA was also observed during decitabine treatment
Identifiants
pubmed: 33203699
pii: 0008-5472.CAN-20-1430
doi: 10.1158/0008-5472.CAN-20-1430
doi:
Substances chimiques
Decitabine
776B62CQ27
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
834-846Commentaires et corrections
Type : CommentIn
Type : CommentOn
Informations de copyright
©2020 American Association for Cancer Research.
Références
Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-Aza-2'-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia. 1997;11:1–5.
Issa J-PJ, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–40.
Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023–36.
Raj K, John A, Ho A, Chronis C, Khan S, Samuel J, et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia. 2007;21:1937–44.
Itzykson R, Thépot S, Eclache V, Quesnel B, Dreyfus F, Beyne-Rauzy O, et al. Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine. Leukemia. 2011;25:1207–9.
Döhner H, Dolnik A, Tang L, Seymour JF, Minden MD, Stone RM, et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia. 2018;32:2546–57.
Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009;23:1019–28.
Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010;5:e9001.
Schoch C, Kohlmann A, Dugas M, Kern W, Hiddemann W, Schnittger S, et al. Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q. Leukemia. 2005;19:1224–8.
Zhao X, Gao S, Wu Z, Kajigaya S, Feng X, Liu Q, et al. Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells. Blood. 2017;130:2762–73.
Zhou L, Opalinska J, Sohal D, Yu Y, Mo Y, Bhagat T, et al. Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. J Biol Chem. 2011;286:25211–23.
Ye Y, McDevitt MA, Guo M, Zhang W, Galm O, Gore SD, et al. Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies. Cancer Res. 2009;69:8482–90.
Sadikovic B, Yoshimoto M, Chilton-MacNeill S, Thorner P, Squire JA, Zielenska M. Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum Mol Genet. 2009;18:1962–75.
Sun Z, Asmann YW, Kalari KR, Bot B, Eckel-Passow JE, Baker TR, et al. Integrated analysis of gene expression, CpG island methylation, and gene copy number in breast cancer cells by deep sequencing. PLoS One. 2011;6:e17490.
Schmelz K, Sattler N, Wagner M, Lübbert M, Dörken B, Tamm I. Induction of gene expression by 5-Aza-2'-deoxycytidine in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but not epithelial cells by DNA-methylation-dependent and -independent mechanisms. Leukemia. 2005;19:103–11.
Jerez A, Sugimoto Y, Makishima H, Verma A, Jankowska AM, Przychodzen B, et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood. 2012;119:6109–17.
Kotini AG, Chang C-J, Boussaad I, Delrow JJ, Dolezal EK, Nagulapally AB, et al. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat Biotechnol. 2015;33:646–55.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.
Lübbert M, Grishina O, Schmoor C, Schlenk RF, Jost E, Crysandt M, et al. Valproate and retinoic acid in combination with decitabine in elderly nonfit patients with acute myeloid leukemia: results of a multicenter, randomized, 2 × 2, phase II trial. J Clin Oncol. 2020;38:257–70.
Blagitko-Dorfs N, Schlosser P, Greve G, Pfeifer D, Meier R, Baude A, et al. Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation. Leukemia. 2019;33:945–56.
Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A. 2005;102:15785–90.
Claus R, Wilop S, Hielscher T, Sonnet M, Dahl E, Galm O, et al. A systematic comparison of quantitative high-resolution DNA methylation analysis and methylation-specific PCR. Epigenetics. 2012;7:772–80.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinforma. 2015;31:166–9.
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.
Jin Y, Tam OH, Paniagua E, Hammell M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinforma. 2015;31:3593–9.
Afgan E, Baker D, van den Beek M, Blankenberg D, Bouvier D, Čech M, et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update. Nucleic Acids Res. 2016;44:W3–10.
Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott-Armstrong NA, Vesuna S, et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods. 2017;14:959–62.
Kreher S, Bouhlel MA, Cauchy P, Lamprecht B, Li S, Grau M, et al. Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2014;111:E4513–4522.
Ramírez F, Ryan DP, Grüning B, Bhardwaj V, Kilpert F, Richter AS, et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016;44:W160–5.
Ramirez F, Wolff J, Grüning B, Bhardwaj V, Ryan D, Dündar F. Deeptools/Hicexplorer: Winter Release [Internet]. 2017.
Yildirim O, Izgu EC, Damle M, Chalei V, Ji F, Sadreyev RI, et al. S-phase enriched non-coding RNAs regulate gene expression and cell cycle progression. Cell Rep. 2020;31:107629.
Schueler J, Greve G, Lenhard D, Pantic M, Edinger A, Oswald E, et al. Impact of the injection site on growth characteristics, phenotype and sensitivity towards cytarabine of twenty acute leukaemia patient-derived xenograft models. Cancers. 2020;12:1349.
Crone J, Glas C, Schultheiss K, Moehlenbrink J, Krieghoff-Henning E, Hofmann TG. Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer Res. 2011;71:2350–9.
Valente D, Bossi G, Moncada A, Tornincasa M, Indelicato S, Piscuoglio S, et al. HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity. Oncotarget. 2015;6:10320–34.
Yao CJ, Works K, Romagnoli PA, Austin GE. Effects of overexpression of HBP1 upon growth and differentiation of leukemic myeloid cells. Leukemia. 2005;19:1958–68.
Pan K, Chen Y, Roth M, Wang W, Wang S, Yee AS, et al. HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence. Mol Cell Biol. 2013;33:887–903.
Bustamante Rivera YY, Brütting C, Schmidt C, Volkmer I, Staege MS. Endogenous retrovirus 3 - history, physiology, and pathology. Front Microbiol. 2017;8:2691.
An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
Brocks D, Schmidt CR, Daskalakis M, Jang HS, Shah NM, Li D, et al. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat Genet. 2017;49:1052–60.
Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, et al. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018;93:E125–7.
Blum S, Greve G, Lübbert M. Innovative strategies for adverse karyotype acute myeloid leukemia. Curr Opin Hematol. 2017;24:89–98.
Stomper J, Lübbert M. Can we predict responsiveness to hypomethylating agents in AML?. Semin Hematol. 2019;56:118–24.
Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162:974–86.
Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.
Ohtani H, Ørskov AD, Helbo AS, Gillberg L, Liu M, Zhou W, et al. Activation of a subset of evolutionarily young transposable elements and innate immunity are linked to clinical responses to 5-azacytidine. Cancer Res. 2020;80:2441–50.
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670–7.
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs. conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–9.
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617–29.