Characterization of the molecular basis for combined epigenetic treatment and BCL2 inhibition in myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML)

骨髓增生异常综合征 (MDS) 和继发性急性髓系白血病 (sAML) 联合表观遗传学治疗和 BCL2 抑制的分子基础特征

• 批准号: 406044709
• 负责人: Dr. Stephan Bohl
• 金额: --
• 依托单位: Klinik für Innere Medizin III
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406044709?language=en
• 关键词: Characterization; molecular; basis; combined; epigenetic

Myelodysplastic syndrome (MDS) is a clonal disorder arising from transformed hematopoietic stem cells. MDS tends to evolve into secondary acute myeloid leukemia (sAML) which is often resistant to chemotherapy and therefore associated with a very short life expectancy. Due to the primary older age at diagnosis most patient are only eligible for hypomethylating agents (HMA) treatment like azacitidine (AZA) and decitabine. However the response rates are low and even patients achieving a complete response in general relapse over time despite continuous HMA maintenance treatment. So far, the development of rational HMA combination therapies has been limited by a lack of precise understanding of mechanisms underlying treatment response and drug resistance. However, since expression of mitochondrial BCL2 proteins, protecting cells from diverse stress challenges including chemotherapy, seems to be relevant for HMA response, BCL2 inhibiting drugs like venetoclax may provide a promising therapeutic addition for outcome improvement. Interestingly the balance between proapoptotic and antiapoptotic BCL2 family proteins shifts in patients that progress from low-risk to high-risk MDS and sAML. However, it remains unclear how certain genetic and epigenetic aberrations in myeloid malignancies influence mitochondrial mediated apoptosis.Therefore the major aim of the proposed study is to better characterize the molecular basis for combined epigenetic and antiapoptotic treatment in myeloid malignancies. In the first part we will study the molecular basis of sensitivity to BCL2 antagonism in MDS/sAML cell lines and in primary patient samples by BH3 profiling and how this sensitivity can be modulated by AZA. This will potentially give us further insights into the alterations of the mitochondrial apoptotic pathway induced by venetoclax, AZA and the combination of both drugs. Next, we will examine the impact of individual MDS/sAML associated genetic aberrations on mitochondrial priming and sensitivity to BCL2 inhibition. In order to clarify the potential synergistic effect of AZA and venetoclax we will study the differently expressed genes prior and after treatment with AZA in several cell lines and determine how these genes influence BCL2 inhibition. These experiments together with the data obtained in the first aim will possibly inform us about the influence of specific gene mutations on mitochondrial priming and sensitivity to venetoclax and AZA. Later on, we will assess whether dynamic BH3 profiling can predict response to venetoclax and AZA in patients. For that purpose, profiling will be performed in samples from patients treated within two clinical trials investigating AZA +/- venetoclax in high-risk MDS patients.

骨髓增生异常综合征（MDS）是一种由造血干细胞转化引起的克隆性疾病。MDS倾向于演变成继发性急性髓细胞白血病（sAML），其通常对化疗具有抗性，因此与非常短的预期寿命相关。由于诊断时的主要年龄较大，大多数患者仅适合低甲基化药物（HMA）治疗，如阿扎胞苷（AZA）和地西他滨。然而，缓解率很低，即使是达到完全缓解的患者，尽管进行了连续的HMA维持治疗，一般也会随时间复发。到目前为止，合理的HMA联合治疗的发展受到缺乏对治疗反应和耐药性机制的精确理解的限制。然而，由于线粒体BCL 2蛋白的表达，保护细胞免受包括化疗在内的各种应激挑战，似乎与HMA反应相关，因此BCL 2抑制药物如维奈托克可能为改善结果提供有希望的治疗添加。有趣的是，在从低风险进展到高风险MDS和sAML的患者中，促凋亡和抗凋亡BCL 2家族蛋白之间的平衡发生了变化。然而，目前还不清楚某些遗传和表观遗传异常在髓系恶性肿瘤的影响线粒体介导的apoptosis，因此，拟议的研究的主要目的是更好地表征的分子基础，在髓系恶性肿瘤的联合表观遗传和抗凋亡治疗。在第一部分中，我们将通过BH 3谱研究MDS/sAML细胞系和原发性患者样本中对BCL 2拮抗作用的敏感性的分子基础，以及这种敏感性如何通过AZA调节。这将潜在地使我们进一步了解由venetoclax、AZA以及两种药物的组合诱导的线粒体凋亡途径的改变。接下来，我们将研究个体MDS/sAML相关遗传畸变对线粒体启动和对BCL 2抑制的敏感性的影响。为了阐明AZA和venetoclax的潜在协同作用，我们将研究AZA处理前后几种细胞系中不同表达的基因，并确定这些基因如何影响BCL 2抑制。这些实验以及在第一个目标中获得的数据可能会告诉我们特定基因突变对线粒体启动和对维奈托克和AZA敏感性的影响。稍后，我们将评估动态BH 3谱是否可以预测患者对维奈托克和AZA的反应。为此，将对在两项研究AZA +/-维奈托克治疗高风险MDS患者的临床试验中接受治疗的患者的样本进行分析。