RNA methylation sequencing shows different gene expression signatures for response to azacytidine therapy in high‐grade myelodysplastic syndromes

• Published in: Journal of cellular and molecular medicine 2024-09, Vol.28 (18), p.e70078-n/a
• Main Authors: Gulei, Diana, Moisoiu, Vlad, Kegyes, David, Drula, Rares, Iluta, Sabina, Tigu, Adrian Bogdan, Nistor, Madalina, Jitaru, Ciprian, Bancos, Anamaria, Rotariu, Petra, Popovici, Corina, Dima, Delia, Tomai, Radu, Rus, Ioana, Constantinescu, Catalin, Munteanu, Raluca, Cenariu, Diana, Sezerman, Ugur, Zdrenghea, Mihnea, Cermak, Jaroslav, Einsele, Hermann, Ghiaur, Gabriel, Tomuleasa, Ciprian
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Azacitidine - pharmacology; Azacitidine - therapeutic use; Azacytidine; Bioinformatics; Bone marrow; Cancer; Cloning; Cytogenetics; DNA methylation; DNA Methylation - drug effects; Epigenesis, Genetic - drug effects; Epigenetics; Female; Gene expression; Gene Expression Profiling; Genomes; Genotypes; Hematology; Hemopoiesis; High-Throughput Nucleotide Sequencing; Humans; Male; Malignancy; Medical prognosis; Middle Aged; Myelodysplastic syndrome; myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Next-generation sequencing; Original; Patients; Phenotypes; Prognosis; Proteins; Ribonucleic acid; RNA; RNA Methylation; RNA methylation sequencing; Sequence Analysis, RNA; Stem cells; Transcriptome - drug effects; Transcriptome - genetics
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.70078

Myelodysplastic syndromes (MDS) are myeloid malignancies with heterogeneous genotypes and phenotypes, characterized by ineffective haematopoiesis and a high risk of progression towards acute myeloid leukaemia (AML). Prognosis for patients treated with hypomethylating agents (HMAs), as is azacytidine, the main drug used as frontline therapy for MDS is mostly based on cytogenetics and next generation sequencing (NGS) of the initial myeloid clone. Although the critical influence of the epigenetic landscape upon cancer cells survival and development as well on tumour environment establishment is currently recognized and approached within current clinical practice in MDS, the heterogenous response of the patients to epigenetic therapy is suggesting a more complex mechanism of action, as is the case of RNA methylation. In this sense, the newly emerging field of epitranscriptomics could provide a more comprehensive perspective upon the modulation of gene expression in malignancies, as is the proof‐of‐concept of MDS. We initially did RNA methylation sequencing on MDS patients (n = 6) treated with azacytidine and compared responders with non‐responders. Afterwards, the genes identified were assessed in vitro and afterwards validated on a larger cohort of MDS patients treated with azacytidine (n = 58). Our data show that a more accurate prognosis could be based on analysing the methylome and thus we used methylation sequencing to differentially split high‐grade MDS patients with identical demographical and cytogenetic features, between azacytidine responders and non‐responders.