Translating genomic discoveries to improved outcomes for high risk acute leukemia

摘要 急性白血病是导致年轻人死亡的主要原因。我的研究计划的目标是找出 白血病发生和治疗失败的基因组驱动因素，并通过实验建模获得机制 洞察力能够开发新的诊断和治疗方法，并最终提高治愈率 这种疾病的比率。在上一个项目期间，我确定了白血病的多种亚型，这些亚型导致了 急性淋巴细胞性白血病与家系模糊白血病的分子分类 白血病的基因组多样性与克隆进化；我论证了液-液相分离的作用 在白血病发生方面；我开发了新的治疗方法，使用定向的蛋白质降解 高危白血病的顽固驱动因素。在这项提案中，最初的总体目标保持不变，但 我的研究计划将涉及几个概念上的新研究领域，这些领域是由我的 先前的发现。这些措施包括(1)定义促进因素放松管制推动的机制 T系ALL的白血病发生；(2)研究LMO2激活和STAG2失活是如何伴随的 改变染色质状态以驱动白血病的发生，以及如何利用这一点进行治疗 益处；(3)阐明BCL11B解除调控如何启动原始造血细胞的谱系模糊 白血病；(4)确定融合癌蛋白驱动的液-液相分离(LLP)如何驱动染色质 以及在白血病发生过程中的转录去调控，以及如何将其作为治疗益处的靶点； (5)开发基于分子胶的靶向蛋白质降解策略，以提高儿童治愈率 白血病。这些研究领域探索儿童和成人白血病的中心问题，包括 增强子劫持/解除调控事件驱动白血病发生的机制，白血病是细胞谱系的基础 家族歧义白血病的模糊性，LLP在白血病发生中的机制作用，以及LLP的疗效 降低急性白血病顽固性驱动因素的创新治疗方法。为了实现这些目标，我将 使用创新的实验方法，包括新的工程小鼠模型、单细胞条形码和 谱系追踪，多组基因表达-染色质分析，LLP-凝集物分析，以及开发 独特的分子胶小分子库。这项研究计划将通过与 在这些方法方面有专长的同事。总的来说，这些方法将产生基本的机械论。 洞察力和治疗进展将改善目前难治性高危白血病的治疗。

ABSTRACT Acute leukemia is a leading cause of death in the young. The goal of my research program is to identify the genomic drivers of leukemogenesis and treatment failure, and through experimental modeling gain mechanistic insight to enable the development of new diagnostic and therapeutic approaches, and ultimately improve cure rates for this disease. In the last project period, I identified multiple subtypes of leukemia that led to a revision of the molecular taxonomy of acute lymphoblastic and lineage ambiguous leukemia; I defined the relationship of genomic variegation and clonal evolution in leukemia; I demonstrated the role of liquid-liquid phase separation in leukemogenesis; and I developed new therapeutic approaches using targeted protein degradation directed at intractable drivers of high-risk leukemia. In this proposal, the original overarching goal remains unchanged, but my research program will address several conceptually new areas of research that have been stimulated by my prior discoveries. These include (1) defining the mechanism by which enhancer deregulation drives leukemogenesis in T-lineage ALL; (2) investigating how concomitant LMO2-activating and STAG2-inactivating alterations perturb chromatin state to drive leukemogenesis, and how this may be exploited for therapeutic benefit; (3) elucidating how BCL11B deregulation primes primitive hematopoietic cells for lineage ambiguous leukemia; (4) determining how fusion oncoprotein-driven liquid-liquid phase separation (LLPS) drives chromatin and transcriptional deregulation in leukemogenesis, and how this may be targeted for therapeutic benefit; and (5) developing molecular glue-based targeted protein degradation strategies to improve cure rates for childhood leukemia. These research areas explore central questions in childhood and adult leukemia, including the mechanisms by which enhancer hijacking/deregulation events drive leukemogenesis, the basis of cell lineage ambiguity in lineage ambiguous leukemia, the mechanistic role of LLPS in leukemogenesis, and the efficacy of innovative therapeutic approaches to degrade intractable drivers of acute leukemia. To achieve these goals I will use innovative experimental approaches including novel engineered mouse models, single cell barcoding and lineage tracing, multiomic gene expression-chromatin profiling, LLPS-condensate profiling, and exploitation of a unique small molecule library of molecular glues. This research program will be facilitated by collaborations with colleagues with expertise in these approaches. Collectively, these approaches will yield fundamental mechanistic insight and therapeutic advances that will improve cures for currently intractable high risk leukemias.