Regulation of hematopoietic stem cells and leukemia stem cells by thrombopoietin

血小板生成素对造血干细胞和白血病干细胞的调节

• 批准号: 9242049
• 负责人: Lei Ding
• 金额: $ 39.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242049
• 关键词: Adult; Alleles; Alpha Cell; Bcr-Abl tyrosine kinase; Blood; Bone Marrow; Bone Marrow Cells; Cell Cycle; Cell Maintenance; Cells; Cellular biology; Chronic Myeloid Leukemia; Clinical; Data; Development; Disease; Frequencies; Gene Expression Profiling; Goals; Growth; Hematological Disease; Hematopoietic stem cells; Homeostasis; Human; Imatinib; Immune system; Knock-in; Knock-out; Knowledge; Life; Maintenance; Malignant Neoplasms; Methods; Modeling; Molecular; Mus; Mutation; Nature; Oncogenic; Osteoblasts; Pathway interactions; Phosphotransferases; Property; Refractory; Regulation; Relapse; Research; Resistance; Role; Rosa; Source; Stem cells; Stromal Cells; System; Testing; Therapeutic; Thrombopoietin; Tyrosine; Tyrosine Kinase Inhibitor; bcr-abl Fusion Proteins; cancer stem cell; cell type; design; experimental study; improved; in vivo; inhibitor/antagonist; insight; kinase inhibitor; leukemia; leukemic stem cell; mutant; novel; novel therapeutics; public health relevance; resistance mechanism; self-renewal; targeted treatment; therapeutic target; von Willebrand Factor

 DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) maintain homeostasis of the blood and immune system throughout life. They are tightly regulated by their microenvironmental niche in the bone marrow. Mounting evidence suggests that chronic myeloid leukemia (CML) arise from mutant HSCs. These diseased leukemia stem cells (LSCs) hijack the HSC mechanisms to sustain the cancer growth and cause relapse. Eradication of LSCs is thus pivotal to cure CML. The discovery of the causing active Bcr/abl kinase mutation in CML and the development of tyrosine kinase inhibitors against Bcr/abl have revolutionized the way we treat CML. Tyrosine inhibitors become the first line of treatment against CML. Although tyrosine kinase inhibitors (e.g. imatinib) can manage the disease, they do not eliminate CML-SCs. A major CML-SC resistant mechanism is the protection offered by the bone marrow niche. Elucidating the niche regulatory mechanisms and target the niche protection mechanisms will help eliminate CML-SCs to better treat CML. However, little is known about the LSC niche. The goal of the proposed research is to characterize how thrombopoietin (TPO), an extrinsic factor, regulates HSCs and LSCs. TPO pathway is required for primitive HSC maintenance in mice and humans. It is not known where Tpo-expressing bone marrow cells create a special niche for primitive HSCs. Furthermore it is not known whether TPO pathway is `hijacked' by CML-SCs for their maintenance. Here, we will identify cellular source of TPO in the bone marrow. Then we will test what cells represent functionally important source for HSC maintenance in vivo. Finally, we will functionally test the role of TPO in CML progression with the focus on CML-SCs in vivo. The results of these studies are expected to not only provide new insights on how the bone marrow niche regulates HSC self-renewal and function, but also have the potential to identify therapeutic targets for CML in the niche.

 描述（由应用提供）：造血干细胞（HSC）一生都保持血液和免疫系统的体内稳态。它们受骨髓中的微环境利基市场的严格调节。越来越多的证据表明，慢性髓样白血病（CML）来自突变的HSC。这些解剖的白血病干细胞（LSC）劫持了HSC机制，以维持癌症的生长并减轻。因此，消除LSC是治愈CML的关键。发现CML中引起活跃的BCR/ABL激酶突变的发现以及针对BCR/ABL的酪氨酸激酶抑制剂的发展彻底改变了我们对待CML的方式。酪氨酸抑制剂成为针对CML的第一道治疗。尽管酪氨酸激酶抑制剂（例如伊马替尼）可以治疗该疾病，但它们不能消除CML-SC。 CML-SC的主要耐药机制是骨髓生态位提供的保护。阐明利基调节机制并针对利基保护机制，将有助于消除CML-SC，以更好地治疗CML。但是，对LSC利基市场知之甚少。拟议的研究的目的是表征血小板蛋白（TPO）如何调节HSC和LSC。 TPO途径是小鼠和人类原始HSC维持所必需的。尚不清楚在哪里表达TPO的骨髓细胞会为原始HSC创建特殊的利基市场。此外，尚不清楚CML-SC是否将TPO途径“劫持”。在这里，我们将确定骨髓中TPO的细胞来源。然后，我们将测试哪些单元在体内代表HSC维护在功能上重要的来源。最后，我们将在功能上测试TPO在CML进程中的作用，重点是体内CML-SC。这些研究的结果不仅有望提供有关骨髓细分市场如何调节HSC自我更新和功能的新见解，而且还具有鉴定利基市场中CML的治疗靶标的潜力。