Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting

白血病前期干细胞的分子和细胞调控及其治疗靶向

• 批准号: 10299704
• 负责人: Ulrich Steidl
• 金额: $ 77.62万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299704
• 关键词: Acute Myelocytic Leukemia; Age-Years; Cells; Clinical; Disease; Disease remission; Dysmyelopoietic Syndromes; Dysplasia; Genetic Models; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Malignant - descriptor; Memory; Molecular; Multipotent Stem Cells; Myelogenous; Outcome; Pathogenesis; Patients; Pharmacology; Play; Precancerous Conditions; Premalignant Cell; Process; Property; Regulation; Research; Resolution; Role; Sampling; System; Testing; Therapeutic Intervention; Vision; Work; cell growth regulation; improved; inhibitor/antagonist; leukemia; leukemic stem cell; mouse genetics; mouse model; novel; novel strategies; premalignant; prevent; progenitor; single molecule; stem; stem cell fate; stem cells; subclonal heterogeneity; therapeutic target; therapeutically effective; therapy resistant; tool; transcription factor

ABSTRACT Clinical outcome in MDS and AML has not significantly improved over the past 50 years and cure rates remain below 15% in the majority of patients (~85%) which are >55 years of age. Fundamentally novel approaches are urgently needed to improve our understanding of disease pathogenesis and to enable more effective therapeutic intervention. Evidence over the past 10 years has shown that MDS and AML arise from preleukemic stem cells (preL-SC), preceding the formation of fully transformed leukemia stem cells (LSC). Recent work has uncovered considerable subclonal heterogeneity of preL-SC in MDS and AML and has indicated that stem cell subclonal complexity plays a key role in pathogenesis, progression, and therapeutic resistance. However, the molecular and cellular mechanisms governing these processes are still largely unknown. Transcription factors (TF) have long been recognized as critical regulators of normal and malignant hematopoiesis. Specifically, in MDS and AML transcriptional dysregulation is key to confer the pathognomonic features of cellular dysplasia and a myeloid differentiation block. Cell fate and differentiation decisions as well as the induction of a myeloid bias at the stem cell and multipotent progenitor level, which is one of the earliest cellular properties detected in preL-SC, are governed by transcription factors. In addition, our recent work has discovered an unexpected degree of transcription dynamics and plasticity in hematopoietic stem and progenitors, and that both transcriptional plasticity and transcriptional memory are dysregulated in preL-SC and LSC. Our major research questions/goals are to understand stem cell subclonal dynamics and their regulation in the initiation and progression of MDS and AML, to identify and study mechanisms of transcriptional cooperativity in pre-leukemic stem cells and their therapeutic targeting, and to study transcription dynamics and pre-LSC fate dysregulation at a single-cell and single-molecule resolution. To accomplish these goals we will utilize novel tools for stem cell subclonal analysis in patients, as well as newly developed longitudinal mouse genetic models of preL-SC progression to MDS and AML. In addition, we will leverage recent advances in our ability to directly target key transcription factors by novel first-in-class pharmacological inhibitors, as well as novel experimental tools for the study of transcription dynamics at a single-molecule level in primary stem/progenitor cells from murine models and patients. Overall, our research will delineate the molecular regulation of pre-cancerous cell states in MDS and AML pathogenesis. This will enable their therapeutic targeting, in addition to the elimination of the fully-transformed leukemic clones. Such an approach holds the promise of achieving lasting remissions and potentially cure of MDS and AML. Our long-term vision is that, once we understand the early transformation-initiating mechanisms in pre-cancerous stem cells, it may even be possible to target such pre-cancerous states before the onset of overt leukemia and thus prevent transformation.

抽象的 过去 50 年来，MDS 和 AML 的临床结果并未显着改善，治愈率仍然保持不变 大多数年龄 >55 岁的患者 (~85%) 的患病率低于 15%。根本上新颖的方法是 迫切需要提高我们对疾病发病机制的了解并实现更有效的治疗 干涉。过去10年的证据表明MDS和AML起源于白血病前期干细胞 (preL-SC)，在完全转化的白血病干细胞 (LSC) 形成之前。最近的工作发现 MDS 和 AML 中 preL-SC 存在相当大的亚克隆异质性，表明干细胞亚克隆 复杂性在发病机制、进展和治疗耐药性中起着关键作用。然而，分子 控制这些过程的细胞机制仍然很大程度上未知。转录因子（TF）有 长期以来被认为是正常和恶性造血的关键调节因子。具体来说，在 MDS 和 AML转录失调是赋予细胞发育不良和骨髓细胞异常增殖特征的关键 分化块。细胞命运和分化决定以及干细胞骨髓偏向的诱导 细胞和多能祖细胞水平是 preL-SC 中检测到的最早的细胞特性之一， 受转录因子控制。此外，我们最近的工作发现了意想不到的程度 造血干细胞和祖细胞的转录动态和可塑性，并且转录 preL-SC 和 LSC 中的可塑性和转录记忆失调。我们的主要研究问题/目标 旨在了解干细胞亚克隆动力学及其在 MDS 发生和进展中的调节作用， AML，识别和研究白血病前期干细胞及其转录协同性的机制 治疗靶向，并研究单细胞的转录动力学和前 LSC 命运失调 单分子分辨率。为了实现这些目标，我们将利用干细胞亚克隆分析的新工具 在患者中，以及新开发的 preL-SC 进展为 MDS 的纵向小鼠遗传模型和 反洗钱。此外，我们将利用最近在直接靶向关键转录因子方面的进展 新型一流的药理学抑制剂，以及用于转录研究的新型实验工具 来自小鼠模型和患者的原代干细胞/祖细胞的单分子水平动力学。全面的， 我们的研究将描述 MDS 和 AML 发病机制中癌前细胞状态的分子调控。 除了消除完全转化的白血病克隆之外，这将使他们能够实现治疗靶向。 这种方法有望实现 MDS 和 AML 的持久缓解和治愈。我们的 长期愿景是，一旦我们了解癌前病变的早期转化启动机制 干细胞，甚至有可能在明显的白血病发作之前针对这种癌前状态 从而防止转化。