Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression Journal Article

   

Authors:	Kazachenka, A.; Young, G. R.; Attig, J.; Kordella, C.; Lamprianidou, E.; Zoulia, E.; Vrachiolias, G.; Papoutselis, M.; Bernard, E.; Papaemmanuil, E.; Kotsianidis, I.; Kassiotis, G.
Article Title:	Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression
Abstract:	Background: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear, induction of endogenous retroelements (EREs) has been hypothesised. Methods: Using RNA sequencing (RNA-seq), we compared the transcription of EREs in bone marrow HSCs from a new cohort of MDS and chronic myelomonocytic leukaemia (CMML) patients before and after 5-AZA treatment with HSCs from healthy donors and AML patients. We further examined ERE transcription using the most comprehensive annotation of ERE-overlapping transcripts expressed in HSCs, generated here by De novo transcript assembly and supported by full-length RNA-seq. Results: Consistent with prior reports, we found that treatment with 5-AZA increased the representation of ERE-derived RNA-seq reads in the transcriptome. However, such increases were comparable between treatment responses and failures. The extended view of HSC transcriptional diversity offered by De novo transcript assembly argued against 5-AZA-responsive EREs as determinants of the outcome of therapy. Instead, it uncovered pre-treatment expression and alternative splicing of developmentally regulated gene transcripts as predictors of the response of MDS and CMML patients to 5-AZA treatment. Conclusions: Our study identifies the developmentally regulated transcriptional signatures of protein-coding and non-coding genes, rather than EREs, as correlates of a favourable response of MDS and CMML patients to 5-AZA treatment and offers novel candidates for further evaluation. © 2019 The Author(s).
Keywords:	adult; clinical article; controlled study; treatment outcome; treatment response; aged; treatment failure; chronic myelomonocytic leukemia; human cell; cancer patient; multiple cycle treatment; gene expression; cohort analysis; genetic transcription; cell differentiation; rna; myelodysplastic syndrome; alternative rna splicing; hematopoietic stem cell; azacitidine; rna sequence; genetic regulation; human; priority journal; article; epigenetic repression; endogenous retroelement
Journal Title:	Genome Medicine
Volume:	11
ISSN:	1756-994X
Publisher:	Biomed Central Ltd
Date Published:	2019-12-23
Start Page:	86
Language:	English
DOI:	10.1186/s13073-019-0707-x
PUBMED:	31870430
PROVIDER:	scopus
PMCID:	PMC6929315
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85077047646&doi=10.1186%2fs13073-019-0707-x&partnerID=40&md5=2b98829aa27848a5e1548ebef304fd24
Notes:	Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/159780