The cohesin complex as a tumor suppressor in myeloid leukemia

摘要 急性髓系白血病(AML)是最常见的成人白血病，其特征是过度增殖 异常的髓系祖细胞。急性髓细胞白血病在所有亚型白血病中的存活率仍然很低。 (五年总存活率50%)，这在很大程度上可以归因于治疗进展有限 过去几十年来一直依赖于使用两种非靶向细胞毒性药物的方案：阿糖胞苷和阿糖胞苷 蒽环类药物。大规模的测序工作已经为人类的遗传和表观遗传决定因素提供了新的线索 AML。有趣的是，这些研究发现基因之间的体细胞突变经常共存。 编码粘附素复合亚单位(如STAG2、SMC1A、RAD21和SMC3)并得到很好的鉴定 AML致癌触发因素，如Flt3-ITD、TET2和NPM1。最近的工作证明了一个重要的 粘附素复合体在正常干/祖细胞自我更新和分化、基因调控和 抑制骨髓增生性肿瘤和急性髓系白血病，尽管其背后的确切机制 人们对其功能仍知之甚少。目前认为粘附素可能通过调节肿瘤的形成来抑制肿瘤的形成。 染色质在对自我更新和髓系祖细胞分化至关重要的基因座上的循环。利用已建立的 小鼠和人急性髓系白血病模型，这一应用重点是粘附素的分子机制。 依赖髓系肿瘤抑制，重点是了解新的治疗方法 可以利用这些功能。使用已建立的协议来识别染色质的全基因组变化 拓扑和基因表达，我们建议对粘附素调节的特性进行广泛的表征 染色质的变化驱动着急性髓细胞白血病。此外，最近的研究发现，HDAC8和多聚ADP具有抑制作用 核糖聚合酶(PARP)作为一种有吸引力的靶向治疗方法来治疗粘附素突变的AML患者。 在这里，我们研究靶向药物在粘附素缺陷型AML中的应用，同时广泛地定位 这些特定治疗方法背后的作用机制。最终，这个项目的目标是产生新奇的、预先的 粘附素突变AML的临床疾病模型及其对肿瘤抑制的强烈机制洞察力 这个综合体的功能。

ABSTRACT Acute myeloid leukemia (AML) is the most common adult leukemia characterized by excessive proliferation of abnormal myeloid progenitors. AML continues to have a dismal survival rate amongst all subtypes of leukemia (<50% five-year overall survival rate), which can largely be attributed to limited advances in treatment regimens that, for the last decades, have relied on the use of two non-targeted cytotoxic drugs: cytarabine and anthracycline. Large-scale sequencing efforts have shed new light on genetic and epigenetic determinants of AML. Interestingly, these studies identified a frequent co-occurrence of somatic mutation between genes encoding cohesin complex subunits (such as STAG2, SMC1A, RAD21 and SMC3) and well-characterized AML oncogenic triggers, such as FLT3-ITD, TET2, and NPM1. Recent work has demonstrated an important role for the cohesin complex in normal stem/progenitor self-renewal and differentiation, gene regulation, and suppression of myeloproliferative neoplasms and AML, despite the precise mechanisms underlying these functions remaining poorly understood. It is believed that cohesin may suppress tumor formation by regulating chromatin looping at loci critical for self-renewal and myeloid progenitor differentiation. Utilizing established models of murine and human AML, this application focuses on the molecular mechanisms of cohesin- dependent myeloid tumor-suppression, with an emphasis on understanding novel treatment approaches that can exploit these functions. Using established protocols for identifying genome-wide changes in chromatin topology and gene expression, we propose to undertake an extensive characterization of cohesin-regulated chromatin changes driving AML. Furthermore, recent studies have identified inhibition of HDAC8 and poly-ADP ribose polymerase (PARP) as an attractive targeted treatment approach for cohesin-mutated AML patients. Here we investigate the application of targeted agents in cohesin-deficient AML whilst extensively mapping the mechanisms-of-action underlying these specific treatments. Ultimately, this project aims to generate novel, pre- clinical disease models of cohesin-mutated AML with strong mechanistic insights into the tumor-suppressive function of this complex.