Leukemia stem cell polarity and differentiation therapy

白血病干细胞极性与分化治疗

• 批准号: 10227111
• 负责人: JAMES C MULLOY
• 金额: $ 44.28万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227111
• 关键词: Actins; Acute Myelocytic Leukemia; Adhesions; Affect; Animal Model; Apoptosis; Biology; Bone Marrow; CD34 gene; CDC42 gene; Cell Differentiation process; Cell Polarity; Cell Transplantation; Cell division; Cell physiology; Cells; Chemicals; Chemoresistance; Clinic; Data; Differentiation Therapy; Distributional Activity; Epigenetic Process; Extracellular Matrix; F-Actin; Failure; Gene Deletion; Genetic; Genetic Transcription; Hematopoietic stem cells; Homeostasis; Human; Image; In Vitro; Literature; MLL-AF9; Maintenance; Mediating; Methodology; Microtubules; Modeling; Molecular; Mus; Oncogenes; PARD6A gene; Pathway interactions; Patients; Pharmacology; Plant Roots; Preclinical Testing; Principal Investigator; Recurrent disease; Refractory Disease; Regulation; Reporter; Reporting; Residencies; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Therapeutic; Translations; Transplantation; Tubulin; Work; Xenograft Model; Xenograft procedure; base; bone marrow xenograft; cancer stem cell; chemotherapy; daughter cell; hematopoietic stem cell fate; improved; inhibitor/antagonist; innovation; insight; interdisciplinary approach; knock-down; leukemia; leukemia initiating cell; leukemic stem cell; loss of function; migration; mouse genetics; mouse model; novel; novel strategies; polarity therapy; polymerization; prevent; programs; regeneration potential; rho GTP-Binding Proteins; self-renewal; small hairpin RNA; small molecule; stem cell differentiation; stem cell division; stem cells; tool

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.

摘要： 超过一半的急性髓性白血病（AML）患者死于难治性或复发性白血病。 由于未能根除白血病根源的白血病起始细胞（LIC）而导致的疾病 出现和传播。低收入国家的特点是获得了自我更新的能力， 休眠有助于化疗抗性。这些属性是由两个 内在的、癌基因驱动的因子，以及与细胞外基质相互作用的信号 和可溶性因子在骨髓（BM）中的支持性小生境内。防止 不受欢迎的自我更新潜力和促进低收入国家的差异化计划， 然而，我们对控制LIC的机制的初步了解 居住在利基和自我更新的调节限制了这样一个概念的翻译， 诊所从造血干细胞（HSC）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） 决定了所产生的子细胞的细胞命运， 具有类似再生潜力和不对称分裂的子细胞， 不同命运的细胞根据我们广泛的初步数据和文献，我们 提出了一个新的假设，即细胞内Cdc 42活性调节的LIC极性影响细胞内的 LIC细胞分裂对称性和因此的自我更新/分化潜力。通过使用 一系列高度创新和多学科的方法， 根据共同主要研究者的专业知识，我们将确定Cdc 42调节的关系。 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 Cdc 42活性在协调LIC极性、分裂对称性和分化中的作用将被 确立了习我们将进一步描述Cdc 42介导的调节LIC的信号通路， 极性和分裂模式，并开始临床前测试的新战略的目标 Cdc 42在人AML中作为小鼠异种移植模型中的分化疗法。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 例如单细胞移植与患者来源的白血病样品组合的方法， 定义了细胞极性和分裂对称性的分子基础，以及它们在 确定LIC细胞命运。

项目成果

The chromatin remodeler CHD8 governs hematopoietic stem/progenitor survival by regulating ATM-mediated P53 protein stability.

染色质重塑因子 CHD8 通过调节 ATM 介导的 P53 蛋白稳定性来控制造血干细胞/祖细胞的存活。

• DOI: 10.1182/blood.2020009997
• 发表时间: 2021
• 期刊: Blood
• 影响因子: 20.3
• 作者: Tu,Zhaowei;Wang,Chen;Davis,AshleyK;Hu,Mengwen;Zhao,Chuntao;Xin,Mei;Lu,QRichard;Zheng,Yi
• 通讯作者: Zheng,Yi