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Different Methylation Signatures at Diagnosis in Patients with High-Risk

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Different Methylation Signatures at Diagnosis in Patients with High-Risk Cabezón et al. Clin Epigenet (2021) 13:9 https://doi.org/10.1186/s13148-021-01002-y RESEARCH Open Access Diferent methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival M. Cabezón1,2†, R. Malinverni3†, J. Bargay4, B. Xicoy1,2, S. Marcé1, A. Garrido5, M. Tormo6, L. Arenillas7, R. Coll8, J. Borras4, M. J. Jiménez1, M. Hoyos5, D. Valcárcel9, L. Escoda10, F. Vall‑Llovera11, A. Garcia12, L. L. Font13, E. Rámila14, M. Buschbeck3,15 and L. Zamora1* on behalf of CETLAM group Abstract Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be efective in the treatment of high‑risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in fnding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high‑risk MDS and secondary AML who were included in CETLAM SMD‑09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be diferenti‑ ated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defned by 200 probes, which allowed diferentiating between patients responding and non‑responding to azacitidine (AZA) treatment and a diferent methylation pattern also defned by 200 probes that allowed to diferentiate patients according to their survival. On studying follow‑up samples, we confrmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions: Our fndings suggest that in a subset of specifc CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival. Keywords: Myelodysplastic syndromes, Secondary acute myeloid leukemia, DNA methylation, Hypomethylating agents, Epigenetic drugs, Prognostic factors, Azacitidine *Correspondence: [email protected] Background †M. Cabezón and R. Malinverni: Equal frst authors 1 Hematology Laboratory Service, ICO Badalona‑Hospital Germans Trias Te term epigenetics refers to all the information trans- I Pujol, Myeloid Neoplasms Group, Josep Carreras Leukemia Research mitted through cell division that is not encoded in the Institute (IJC), Badalona, Spain DNA sequence. Te methylation of DNA, encodes some Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Cabezón et al. Clin Epigenet (2021) 13:9 Page 2 of 14 epigenetic information related to the transcriptional contribute to the pathogenesis of the diseases [15, 23– state of genes [1]. DNA methylation is catalyzed by DNA 27]. In the context of epigenetics, altered DNA methyla- methyltransferases (DNMTs) that transfer a methyl tion patterns have been observed in MDS. In particular, group to a cytosine residue (5-methylcytosine) within the hypermethylation of CpG islands and the silencing of a CpG dinucleotide. Te large majority of CpGs in the linked genes appear in early stages of the disease and are genome are methylated and contribute to stable repres- associated with poor prognosis and disease progression sion of repeated sequences in heterochromatin stability [28–30]. Azacitidine has been shown to prolong overall [2]. Regions enriched in CpG, called CpG islands, are also survival compared with conventional care regimens and found in the promoters of genes. Te majority of these thus, it is recommended as frst-line treatment for most CpG islands are unmethylated in cells of normal tissues patients with higher-risk MDS which are not eligible for regardless of their diferentiation state [1]. Tis lack of allogeneic stem cell transplantation [14, 31]. Half of the methylation in promoter-associated CpG islands allows patients do not respond favorably to the treatment and gene expression, if the appropriate transcription factors virtually all responders eventually relapse [32]. A major are present and the chromatin structure allows access to limitation for the clinical management is that several them [3, 4]. Many human diseases, and in particular can- months of treatment are required before the efcacy of cers, are associated with aberrations in the DNA meth- the therapy can be assessed. At present, we lack a robust ylation profle [1, 5–7]. Neoplastic cells frequently display biomarker for predicting treatment response. In par- global DNA hypomethylation with localized hypermeth- ticular, there is debate about the informative potential of ylation of CpG islands [4]. Hypomethylation may play a DNA methylation at diagnosis. Some studies have shown role in carcinogenesis through activation of oncogenes an association between pretreatment DNA methylation [8] and chromosomal instability [9]. In contrast, aber- profles and response to HMA [33, 34], while others have rant hypermethylation of CpG islands in cancer is clearly not [35–37]. associated with gene silencing and contributes to the While HMAs are undoubtedly helpful in the treatment inactivation of tumor suppressor genes [4, 10, 11]. Bay- of MDS patients, there is an urgent need to fnd prog- lin and Jones estimated that the inactivation of tumor nostic and response-predictive biomarkers that could suppressor genes by gaining DNA methylation occurs as determine whether a patient will respond to HMAs. often as their inactivation by mutations [7, 12]. In con- Tis would avoid progression under treatment, the delay trast to genetic alterations, epigenetic changes are poten- of other therapeutical options and the development of tially reversible by pharmacological inhibition of DNA unwanted side efects. To address this need, the aim of methylation and histone deacetylation [13], thus provid- our study was to assess DNA methylation patterns at ing a potential point for therapeutic intervention. diagnosis and follow-up in patients with high-risk MDS Te azanucleosides, azacitidine (AZA) and decitabine, and sAML and determine if there is a methylation pro- are incorporated as analog of cytidine into DNA and fle that distinguishes patients according to treatment inhibit DNA methyltransferase through covalent binding response and overall survival (OS). [14]. As a consequence of this function azanucleosides are commonly referred to as hypomethylating agents Results (HMAs). Patient and sample characteristics Te reactivation of abnormally silenced tumor suppres- Tis study included a total of 75 patients with high sor genes, DNA repair genes, and microRNAs was long risk MDS or sAML. Te main clinical and hemato- thought to be the main mechanism by which HMA exerts logical characteristics of these patients at diagnosis are anti-tumor activity [15–17]. However, more recently, described in Table 1. HMA have shown to up regulate endogenous retrovirus We analyzed 156 bone marrow aspirates that were col- transcripts, which form cytoplasmic double-stranded lected at diagnosis and during follow-up. Of these sam- RNA and trigger autonomous and immune-cell induced ples, 108 were from high-risk MDS and 48 from sAML cell death [18–20]. In addition, azanucleosides induce patients. Te number of samples at diagnosis and follow- cytotoxic efects by impacting on DNA and, in the case of up are shown in Additional fle 1: Table 1. In two patients AZA also RNA, metabolism [21, 22]. follow-up samples were available, but a sample at diag- Myelodysplastic syndromes (MDS) refer to a het- nosis was lacking. Approximately half of all the patients erogeneous group of aging-related myeloid neoplasms received AZA treatment, while the other half under- originating in hematopoietic stem and progenitor cells. went intensive chemotherapy followed or not by ASCT. MDS are characterized by inefective hematopoiesis and Treatment response to AZA was assessed following the increased risk of progression to secondary acute mye- criteria defned by the 2006 IWG for MDS patients [38]. loid leukemia (sAML). Genetic
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