Noncoding RNAs and Their Response Predictive Value in Azacitidine-treated Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia With Myelodysplasia-related Changes.

Michaela Dostalova Merkerova,Jiri Klema,David Kundrat,Anna Jonasova,Andrea Hrustincova,Anh Vu Le,Zdenek Krejcik,Iva Trsova,Jaroslav Cermak,Katarina Szikszai,Monika Belickova

doi:10.21873/cgp.20315

Abstract

Prediction of response to azacitidine (AZA) treatment is an important challenge in hematooncology. In addition to protein coding genes (PCGs), AZA efficiency is influenced by various noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and transposable elements (TEs). RNA sequencing was performed in patients with myelodysplastic syndromes or acute myeloid leukemia before AZA treatment to assess contribution of ncRNAs to AZA mechanisms and propose novel disease prediction biomarkers. Our analyses showed that lncRNAs had the strongest predictive potential. The combined set of the best predictors included 14 lncRNAs, and only four PCGs, one circRNA, and no TEs. Epigenetic regulation and recombinational repair were suggested as crucial for AZA response, and network modeling defined three deregulated lncRNAs (CTC-482H14.5, RP11-419K12.2, and RP11-736I24.4) associated with these processes. The expression of various ncRNAs can influence the effect of AZA and new ncRNA-based predictive biomarkers can be defined.

Highlights

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal malignancies characterized by ineffective hematopoiesis resulting in peripheral cytopenia and hypercellular bone marrow dysplasia
This study focused on the noncoding transcriptome and paid special attention to the examination of various classes of ncRNAs as predictive markers of the AZA response and compared their power to predict the response with the predictive power of protein coding genes (PCGs)
Multiple publications have described alterations of PCGs involved in chromatin modification, DNA methylation, RNA splicing, cohesin complex, transcription factors, cell signaling, and DNA damage [40]

Summary

Introduction

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal malignancies characterized by ineffective hematopoiesis resulting in peripheral cytopenia and hypercellular bone marrow dysplasia. Because DNA hypermethylation can contribute to tumorigenesis by silencing tumor suppressor genes, it was supposed that the methylation pattern may be predictive of AZA response. Both global and gene-specific hypermethylation have been performed in MDS [13, 14], little relation between the degree of demethylation following hypomethylating treatment and hematologic response has been evidenced [15]. To provide biological insights into the contribution of noncoding RNAs (ncRNAs) to the AZA response or resistance and to propose novel appropriate molecular markers able to predict the response, whole transcriptome RNA sequencing (RNA-seq) was performed in CD34+ BM cells in patients with higherrisk MDS and AML with myelodysplasia-related changes (AML-MRC) before AZA therapy. To the authors’ knowledge, this is the first study addressing and integrating transcriptional data of these molecules in MDS

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