Different gene sets are associated with azacitidine response in vitro and myelodysplastic syndrome patients

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders and characterized by dysplasia, ineffective hematopoiesis and predisposition to secondary acute myeloid leukemia (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond and all patients eventually relapse. Response predicting biomarkers and combinatorial drugs targets enhancing response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including four genes encoding components of ISWI chromatin remodelling complex pointing towards a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the association of expression of a gene panel in bone marrow samples collected at diagnosis of 36 MDS patients. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as SMARCA5 as positive indicator for AZA response, or NSUN3 that correlated with increased overall survival. Taken together we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely non-overlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.

骨髓增生异常综合征（Myelodysplastic syndromes, MDS）是一类异质性造血系统疾病，以造血细胞发育异常、无效造血以及继发急性髓系白血病（secondary acute myeloid leukemia, sAML）易感倾向为核心特征。阿扎胞苷（Azacitidine, AZA）是不符合异基因骨髓移植指征的高危MDS患者的标准治疗方案。然而，仅半数患者可获得临床应答，且所有患者最终均会出现疾病复发。目前亟需可预测治疗应答的生物标志物，以及能够增强疗效并延长应答持续时间的联合药物靶点。
本研究采用双维度研究策略：其一，我们评估了编码染色质调控因子的基因对阿扎胞苷应答的调控能力，成功验证了多个可通过基因抑制影响细胞对阿扎胞苷应答的基因，其中包含4个编码ISWI染色质重塑复合物组分的基因，提示该复合物具备特定功能并存在共脆弱性；其二，我们采用经典队列分析方法，对36例初诊MDS患者的骨髓样本中一组基因的表达相关性进行了检测。该基因组合涵盖本研究鉴定的阿扎胞苷调控基因、已知参与阿扎胞苷代谢的基因，以及既往已报道的候选调控基因。
除验证多项既往研究结论外，本研究还鉴定出多个全新的关联特征：例如SMARCA5可作为阿扎胞苷应答的阳性指示因子，NSUN3则与患者总生存期延长呈显著正相关。综上，我们在体外实验及患者队列样本中均鉴定出多个与阿扎胞苷应答相关的基因。这些基因群体之间重叠度极低，提示在开发联合药物靶点及疗效预测生物标志物时，需针对性选用不同的基因集合。