Abstract
BackgroundMyelodysplastic 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.MethodsUsing 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.ResultsConsistent 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.ConclusionsOur 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.
Highlights
Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs)
RNA sequencing (RNA-seq) data generated from highly purified bone marrow CD34+ HSCs (Additional file 2: Figure S1) were analysed using a previously established pipeline that quantifies the transcription of repetitive elements together with annotated genes [45]
Genes upregulated in healthy HSCs included several involved in B cell differentiation, such as RAG1 and RAG2 mediating immunoglobulin gene segment recombination, and the B cell-specific transcription factor PAX5, whereas those upregulated in AML, and to a lesser extent in MDS and chronic myelomonocytic leukaemia (CMML) HSCs were involved in myeloid differentiation, such as the cathepsins CTSA and CTSD (Fig. 1a)
Summary
Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Epigenetic drugs (epidrugs) that can reverse the repressive state of DNA hypermethylation, such as 5azacytidine (5-AZA) and 5-aza-2′-deoxycytidine (decitabine), have been the mainstay of treatment for higherrisk MDS and for older, unfit AML patients. Being cytidine analogues, both 5-AZA and decitabine are incorporated into the DNA of highly proliferating cells leading to a genome-wide decrease of methylation levels, whereas 5-AZA is incorporated into RNA [9, 10]. A favourable outcome of 5-AZA treatment is observed in less than half of treated patients, almost all of whom relapse [11, 12], and these disparate responses cannot yet be predicted
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