Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival

Marta Cabezón ,Leonor Arenillas ,M.j Jiménez ,Rosa Coll ,Josep Borrás ,Llorens Font ,Blanca Xicoy ,Ferrán Vall-Llovera ,Elena Rámila ,Montserrat Hoyos ,Antoni García ,Mar Tormo ,Ana Garrido ,Roberto Malinverni ,Marcus Buschbeck ,Joan Bargay ,Lourdes Escoda ,Sílvia Marcé ,David Valcárcel ,Lurdes Zamora

doi:10.1186/s13148-021-01002-y

Abstract

BackgroundEpigenetic therapy, using hypomethylating agents (HMA), is known to be effective 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 finding 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.ResultsUnsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed 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.ConclusionsOur findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Highlights

Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective 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
Patient and sample characteristics This study included a total of 75 patients with high risk MDS or secondary acute myeloid leukemia (sAML)
Treatment response to AZA was assessed following the criteria defined by the 2006 International Working Group (IWG) for MDS patients [38]

Summary

Introduction

Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective 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. Regions enriched in CpG, called CpG islands, are found in the promoters of genes The majority of these CpG islands are unmethylated in cells of normal tissues regardless of their differentiation state [1]. This lack of methylation in promoter-associated CpG islands allows gene expression, if the appropriate transcription factors are present and the chromatin structure allows access to them [3, 4]. Aberrant hypermethylation of CpG islands in cancer is clearly associated with gene silencing and contributes to the inactivation of tumor suppressor genes [4, 10, 11]. In contrast to genetic alterations, epigenetic changes are potentially reversible by pharmacological inhibition of DNA methylation and histone deacetylation [13], providing a potential point for therapeutic intervention

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