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.

中文翻译：

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骨髓增生异常综合征的表观遗传治疗与细胞分化相关，独立于内源性逆转录因子去抑制。


背景骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的特征是骨髓造血干细胞（HSC）的异常表观遗传抑制和分化。逆转表观遗传抑制的药物，如 5-氮杂胞苷 (5-AZA)，可使一半接受治疗的患者的血液学改善。尽管治疗成功的机制尚不清楚，但已假设诱导内源性逆转录因子（ERE）。方法 使用 RNA 测序 (RNA-seq)，我们比较了一组新的 MDS 和慢性粒单核细胞白血病 (CMML) 患者在 5-AZA 治疗前后的骨髓 HSC 中 ERE 的转录，以及健康供体和 AML 患者的 HSC 的转录情况。我们使用 HSC 中表达的 ERE 重叠转录本的最全面注释进一步检查了 ERE 转录，这些转录本是通过从头转录本组装生成的，并得到全长 RNA 测序的支持。结果与之前的报告一致，我们发现 5-AZA 治疗增加了转录组中 ERE 衍生的 RNA-seq 读数的代表性。然而，治疗反应和失败之间的这种增加是可比的。从头转录组装提供的 HSC 转录多样性的扩展观点反对将 5-AZA 响应 ERE 作为治疗结果的决定因素。相反，它发现发育调节基因转录物的治疗前表达和选择性剪接可以作为 MDS 和 CMML 患者对 5-AZA 治疗反应的预测因子。 结论 我们的研究确定了蛋白质编码和非编码基因（而不是 ERE）的发育调节转录特征，与 MDS 和 CMML 患者对 5-AZA 治疗的良好反应相关，并为进一步评估提供了新的候选者。