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 haematologica...
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doaj-bc18ef2bdea645658e48631f6ae61c142020-12-27T12:04:21ZengBMCGenome Medicine1756-994X2019-12-0111111810.1186/s13073-019-0707-xEpigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepressionAnastasiya Kazachenka0George R. Young1Jan Attig2Chrysoula Kordella3Eleftheria Lamprianidou4Emmanuela Zoulia5George Vrachiolias6Menelaos Papoutselis7Elsa Bernard8Elli Papaemmanuil9Ioannis Kotsianidis10George Kassiotis11Retroviral Immunology, The Francis Crick InstituteRetrovirus-Host Interactions, The Francis Crick Institute, The Francis Crick InstituteRetroviral Immunology, The Francis Crick InstituteDepartment of Haematology, Democritus University of Thrace Medical SchoolDepartment of Haematology, Democritus University of Thrace Medical SchoolDepartment of Haematology, Democritus University of Thrace Medical SchoolDepartment of Haematology, Democritus University of Thrace Medical SchoolDepartment of Haematology, Democritus University of Thrace Medical SchoolCenter for Molecular Oncology, Center for Heme Malignancies and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer CenterCenter for Molecular Oncology, Center for Heme Malignancies and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer CenterDepartment of Haematology, Democritus University of Thrace Medical SchoolRetroviral Immunology, The Francis Crick InstituteAbstract 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.https://doi.org/10.1186/s13073-019-0707-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anastasiya Kazachenka George R. Young Jan Attig Chrysoula Kordella Eleftheria Lamprianidou Emmanuela Zoulia George Vrachiolias Menelaos Papoutselis Elsa Bernard Elli Papaemmanuil Ioannis Kotsianidis George Kassiotis |
spellingShingle |
Anastasiya Kazachenka George R. Young Jan Attig Chrysoula Kordella Eleftheria Lamprianidou Emmanuela Zoulia George Vrachiolias Menelaos Papoutselis Elsa Bernard Elli Papaemmanuil Ioannis Kotsianidis George Kassiotis Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression Genome Medicine |
author_facet |
Anastasiya Kazachenka George R. Young Jan Attig Chrysoula Kordella Eleftheria Lamprianidou Emmanuela Zoulia George Vrachiolias Menelaos Papoutselis Elsa Bernard Elli Papaemmanuil Ioannis Kotsianidis George Kassiotis |
author_sort |
Anastasiya Kazachenka |
title |
Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
title_short |
Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
title_full |
Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
title_fullStr |
Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
title_full_unstemmed |
Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
title_sort |
epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2019-12-01 |
description |
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. |
url |
https://doi.org/10.1186/s13073-019-0707-x |
work_keys_str_mv |
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