Targeting metabolism in leukemic stem cells

靶向白血病干细胞的代谢

基本信息

批准号：
8619417
负责人：
CHENG-KUI QU
金额：
$ 16.97万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619417
关键词：
Acute Myelocytic Leukemia Affect Antibiotics Area Bioenergetics Blast Cell Bone Marrow Cells CDKN1C gene Cell Cycle Cell Respiration Cell Survival Cell physiology Commit Development Disease Drug resistance Embryo FLT3 gene Fibroblasts Funding Opportunities Glycolysis Goals Growth Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Human In Vitro Knockout Mice Lead Leukemic Cell Maintenance Malignant Neoplasms Metabolic Metabolic stress Metabolism Methodology Mitochondria Modeling NIH Program Announcements National Cancer Institute Neoplasm Metastasis Oncogenes Organ Oxidative Phosphorylation PTEN gene Pharmaceutical Preparations Phosphoric Monoester Hydrolases Play Population Process Property Publishing Recurrent disease Research Activity Research Project Grants Risk Role Source Staging Stem cells Stress System Techniques Testing Therapeutic Agents Therapeutic Effect Work Xenograft Model anticancer research base cancer cell dental agent embryonic stem cell inhibitor/antagonist innovation inorganic phosphate leukemia leukemic stem cell mouse model novel novel strategies novel therapeutics precursor cell prevent progenitor programs public health relevance research study response self-renewal sensor septic stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML), a clonal hematological malignancy, originates from and is sustained by a small population of self-renewing precursor cells - leukemic stem cells (LSCs). This disease is organized by a hierarchy system where the bulk of leukemic cells, i.e. blasts at various stages of maturation, are generated from LSCs through the process known as repopulation/differentiation. Here, leukemic blasts are rapidly expanded and evoke devastating pathological effects in multiple organs. LSCs are also the major source for metastasis, drug resistance, and relapse of the disease. This immortal reservoir of cancer cells display extremely low proliferation rates and likely are not eradicated by current treatments. Clearly, a novel approach focused on the unique properties of LSCs is needed. Our recent studies have established a critical role of PTPMT1, a mitochondrial PTEN-like phosphotidylinositide phosphate phosphatase, in differentiation of embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs). This phosphatase is essential for the metabolic transition from glycolysis to mitochondrial oxidative phosphorylation required for ESC and HSC differentiation, owing to the quickly rising energy demand during this process. PTPMT1 depletion alters mitochondrial aerobic metabolism and causes bioenergetic stress, leading to cell cycle changes and thus a differentiation block in ESCs and HSCs (without affecting cell survival). Intriguingly, PTPMT1 is dispensable for differentiated embryonic fibroblasts and lineage-committed hematopoietic progenitors. These studies led to the identification of a stem cell-specific differentiation checkpoint activated by bioenergetic stress. As LSCs share certain properties with normal HSCs, including metabolic reprogramming during differentiation, we hypothesize that PTPMT1 plays a similarly important role in the progression of LSCs to the blast stage and that LSC differentiation/repopulation capabilities can be blocked via activation of the energetic stress-induced differentiation checkpoint through inhibition of PTPMT1. We plan to test our hypothesis and accomplish the objective of this application by pursuing two aims. 1). To determine the role of PTPMT1 in LSC differentiation/repopulation. 2). To test for the therapeutic effects of a PTPMT1 inhibitor in the AML xenograft model. This application tests a novel idea, i.e. blocking LSC function by inducing metabolic stress, which represents an innovative approach to potentially control AML. In addition, as the PTPMT1 selective inhibitor to be tested is also a known antibiotic, this work may lead to the identificatin of a new therapeutic agent in eliciting a differentiation block in LSCs, thus preventing leukemic blast formation in AML.

描述（由申请人提供）：急性髓样白血病（AML），一种克隆血液性恶性肿瘤，起源于少数自我更新前体细胞 - 白血病干细胞（LSC）。该疾病是由层次结构系统组织的，该系统大部分白血病细胞（即在成熟的各个阶段的爆炸）通过LSC通过称为重生/分化的过程产生。在这里，白血病爆炸迅速扩大，并引起多个器官中毁灭性的病理影响。 LSC也是转移，耐药性和疾病复发的主要来源。这种不朽的癌细胞储层表现出极低的增殖率，并且可能不会被当前处理消除。显然，需要一种针对LSC的独特特性的新颖方法。我们最近的研究确立了PTPMT1（线粒体PTEN样磷酸苷磷酸磷酸磷酸酶）在胚胎干细胞（ESC）和造血干细胞（HSC）中的关键作用。该磷酸酶对于从糖酵解到ESC和HSC分化所需的线粒体氧化磷酸化的代谢过渡至关重要，这是由于此过程中能量需求的迅速上升。 PTPMT1耗竭会改变线粒体有氧代谢并引起生物能应力，从而导致细胞周期变化，从而导致ESC和HSC中的分化阻滞（不影响细胞存活）。有趣的是，PTPMT1对于分化的胚胎成纤维细胞和谱系造血祖细胞是可分配的。这些研究导致了通过生物能应力激活的干细胞特异性分化检查点的鉴定。由于LSC与正常的HSC共享某些特性，包括在分化过程中代谢重编程，因此我们假设PTPMT1在LSC向爆炸阶段的发展中起着相似的重要作用，并且可以通过通过抑制PTPMT的抑制抑制ptpmt的抑制作用来激活LSC分化/重新构型能力。我们计划通过追求两个目标来检验我们的假设并实现此应用的目标。 1）。确定PTPMT1在LSC分化/重生中的作用。 2）。测试AML异种移植模型中PTPMT1抑制剂的治疗作用。该应用程序测试了一种新颖的想法，即通过诱导代谢应力来阻止LSC功能，这代表了潜在控制AML的创新方法。另外，由于要测试的PTPMT1选择性抑制剂也是已知的抗生素，因此这项工作可能导致新的治疗剂在引发LSC中的分化块时鉴定出来，从而防止AML中的白血病形成。