Leukemia stem cell polarity and differentiation therapy

摘要： 超过一半的急性髓系白血病(AML)患者死于难治性或复发 由于未能根除白血病根部的白血病启动细胞(LIC)而导致的疾病 羽化和繁殖。LIC的特点是获得自我更新的能力和 休眠是化疗抵抗的原因之一。这些属性由两个 内在的、癌基因驱动的因子以及与细胞外基质相互作用产生的信号 以及骨髓(BM)中支持性利基内的可溶性因子。防止发生 LIC中不需要的自我更新潜力和促进差异化计划将具有 治疗的好处；然而，我们对LIC控制机制的初步了解 居住在利基市场及其自我更新的规定限制了将这种概念翻译到 诊所。从造血干细胞(HSCs)的调节机制中吸取的教训提供了 有用的线索：一个模型表明干细胞分裂的类型(对称与不对称) 确定生成的子细胞的单元格命运，对称分裂会导致 具有相似再生能力和不对称分裂的子代细胞导致子代 有着不同命运的细胞。基于我们广泛的初步数据和文献，我们 提出了一种新的假说，即受细胞内CDC42活性调节的LIC极性影响 LIC细胞分裂对称性，因此具有自我更新/分化潜能。通过使用 一系列高度创新和多学科的方法结合了优势和 联合首席调查员的专业知识，我们将确定受管制的cdc42的关系。 LIC自我更新和分化中的细胞极性和分裂对称性。潜在的因果关系 CDC42活性在协调LIC极性、分裂对称性和分化中的作用将是 已经成立了。我们将进一步描述调控LIC的CDC42介导的信号通路 极性和划分模式，并开始对新的靶向策略进行临床前测试 人急性髓系白血病在小鼠异种移植模型中的分化治疗。这些研究将 使用最先进的动物模型、成像、化学生物学、小鼠遗传学和干细胞 单细胞移植与患者来源的白血病样本相结合的方法 定义细胞极性和分裂对称性的分子基础及其在 决定LIC细胞的命运。

Abstract: Over half of all patients with acute myeloid leukemia (AML) succumb to refractory or relapsed disease due to a failure to eradicate the leukemia initiating cells (LICs) at the root of leukemia emergence and propagation. LICs are characterized by acquired capacity for self-renewal and dormancy contributing to chemotherapy resistance. These attributes are conferred by both intrinsic, oncogene-driven factors, as well as signals from interactions with extracellular matrix and soluble factors within a supportive niche in the bone marrow (BM). Preventing the undesired self-renewal potential and promoting a differentiation program in LICs will have therapeutic benefits; however, our rudimentary understanding of the mechanism controlling LIC residency in the niche and its self-renewal regulation limits translation of such a concept to the clinic. A lesson from the regulatory mechanism of hematopoietic stem cells (HSCs) provides useful clues: one model suggests that the type of stem cell division (symmetric vs. asymmetric) determines the cell fate of the resulting daughter cells, with symmetric division resulting in daughter cells with similar regenerative potential and asymmetric division leading to daughter cells with dissimilar fates. Based on our extensive preliminary data and the literature, we propose a novel hypothesis that LIC polarity regulated by intracellular Cdc42 activity affects the LIC cell division symmetry and consequently the self-renewal/differentiation potential. By using an array of highly innovative and multi-disciplinary approaches combining the strength and expertise of the co-principal investigators, we will determine the relationship of Cdc42 regulated cell polarity and division symmetry in LIC self-renewal and differentiation. A potentially causal role of Cdc42 activity in coordinating LIC polarity, division symmetry and differentiation will be established. We will further delineate the Cdc42-mediated signaling pathways that regulate LIC polarity and mode of division, and begin a preclinical testing of the novel strategy of targeting Cdc42 in human AML as a differentiation therapy in mouse xenograft models. The studies will use state of the art animal models, imaging, chemical biology, mouse genetics, and stem cell methodologies like single cell transplants combined with patient derived leukemia samples to define the molecular basis of cell polarity and divisional symmetry and their causal role in determining LIC cell fate.