Identification and targeting of pathways separating healthy stem cell aging from malignant transformation

鉴定和靶向区分健康干细胞衰老与恶性转化的途径

• 批准号: 10461093
• 负责人: Britta Will
• 金额: $ 38.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461093
• 关键词: Acute Myelocytic Leukemia; Adult; Age; Aging; Autophagocytosis; Biosensor; Blood; Blood Cells; Cell Compartmentation; Cell physiology; Cells; Chemicals; Chronic stress; Clinical; Cytoplasmic Organelle; Cytoplasmic Protein; DNA Damage; Data; Defect; Development; Disease; Dysmyelopoietic Syndromes; Eating; Elderly; Evolution; Functional disorder; Genetic; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Human; Human Cell Line; Impairment; Intracellular Accumulation of Lipids; Knowledge; Link; Lysosomes; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane Proteins; Modeling; Molecular; Molecular Chaperones; Mus; Myeloproliferative disease; Non-Malignant; Pathology; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiological; Premature aging syndrome; Process; Protein Isoforms; Proteins; RNA Splicing; Reactive Oxygen Species; Recycling; Reporter; Resolution; Role; System; Testing; Therapeutic; Tissues; Variant; adult stem cell; aged; base; cancer stem cell; cell type; curative treatments; healthy aging; inhibition of autophagy; inhibitor; insight; leukemogenesis; lipid metabolism; mouse model; novel therapeutic intervention; novel therapeutics; premalignant; prospective; self-renewal; small molecule; stem cell aging; stem cell function; stem cells; tool; wasting

ABSTRACT Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are generally incurable hematologic malignancies, originating from aberrant hematopoietic stem cells (HSCs). These diseases occur mainly in the elderly and are preceded by an often-unrecognized precancerous phase, which can last for years and is hallmarked by a progressively changing HSC compartment. Such molecularly and functionally diverging stem cells, termed pre-leukemic stem cells (pre-LSCs), harbor a higher propensity to undergo malignant transformation. Mechanisms that separate the healthy aging process from cancer evolution are incompletely resolved. This gap in our knowledge poses a significant challenge for the development of curative therapies for myeloid malignancies for which cure rates have mostly remained below 30% over the last decades. Our study will investigate the role of chaperone-mediated autophagy (CMA), a highly selective subtype of autophagy, which has not been systematically characterized in the hematopoietic system thus far. Contrary to macroautophagy, CMA specifically degrades proteins containing defined recognition motifs (“KFERQ”, and variants), and maintains integrity and proper function of many cell types during chronic stress and aging. CMA declines in and critically contributes to several age-associated pathologies, yet its role in leukemogenesis and cancer stem cell evolution is unknown. Using new genetic mouse models, we have obtained exciting preliminary data demonstrating that CMA sustains the function of healthy HSCs. Furthermore, we found that impairment of CMA increased pre-LSC function that appears to be linked with increased levels of reactive oxygen species, accumulating in CMA-deficient stem cells. For this study, we hypothesize that CMA protects against stem cell dysfunction and malignant transformation. We will utilize a complementary model set consisting of genetic mouse models, human cell lines and primary patient-derived cells for the study of (1) CMA activation patterns in healthy HSCs and pre-LSCs (leveraging a CMA reporter mouse and lentiviral CMA biosensors for primary human cells), (2) molecular and (3) functional consequences of CMA inactivation and stimulation. We will also test a new chemical CMA activator tool compound for its efficacy to promote healthy HSCs and impair pre-LSCs, which could be further developed for clinical use. Our study will provide new insights into a molecular mechanism declining during aging and predisposing adult tissue-specific stem cells to malignant transformation, which will have important implications for the development of new therapeutic strategies for targeting autophagy in myeloid malignancies, and possibly other stem cell-derived cancers.

抽象的 骨髓增生综合征（MDS）和急性髓性白血病（AML）通常是无法治愈的血液学 恶性肿瘤，起源于异常的造血干细胞（HSC）。这些疾病主要发生在 老年人，然后是经常被认可的癌前阶段，该阶段可以持续数年，并且是标志性的 通过逐步更改HSC隔间。这种分子和功能分化的干细胞称为 白血病前干细胞（前LSC）具有更高的可靠性，可进行恶性转化。 将健康的衰老过程与癌症进化分开的机制无法完全解决。这个差距 在我们的知识中，骨髓恶mig鼠的治疗疗法的开发面临重大挑战 在过去的几十年中，治愈率的大部分一直低于30％。 我们的研究将研究伴侣介导的自噬（CMA）的作用，这是一种高度选择性的亚型 迄今为止，自噬在造血系统中尚未系统地表征。与 大量噬菌体，CMA专门降解含有定义识别基序的蛋白质（“ KFERQ”和 变体），并在慢性应激和衰老期间保持许多细胞类型的完整性和正常功能。 CMA 下降并严重促进了几种与年龄相关的病理，但其在白血病发生和 癌症干细胞的进化尚不清楚。使用新的遗传鼠标模型，我们获得了令人兴奋的初步 数据表明CMA维持健康HSC的功能。此外，我们发现 CMA提高了LSC函数，似乎与活性氧的水平增加有关， 积累在CMA缺陷型干细胞中。在这项研究中，我们假设CMA可以预防干细胞 功能障碍和恶性转化。 我们将利用由遗传小鼠模型，人类细胞系和主要的完整模型集 患者衍生的细胞研究（1）健康HSC和LSC中的CMA激活模式（利用A CMA报告基因小鼠和慢病毒CMA生物传感器用于原代人细胞），（2）分子和（3）功能 CMA失活和刺激的后果。我们还将测试一种新的化学CMA激活剂工具 促进健康的HSC和损害前LSC的有效性的复合性，可以进一步开发 临床用途。 我们的研究将提供有关在衰老和诱发成人期间下降的分子机制的新见解 组织特异性干细胞对恶性转化，这将对 制定针对髓样恶性肿瘤自噬的新治疗策略以及其他可能的其他治疗策略 干细胞衍生的癌症。