Understanding Hemotopoietic Neoplasias using Humanized Mice

生物医学研究的最终目的是研究人类，目的是改善人类健康。然而，由于无法进行侵入性实验工作以确定过程之间的因果关系，对人类的研究受到严重影响。小鼠模型在描述人类恶性转化和疾病驱动力的关键方面发挥着重要作用。然而，它们很少能代表人类疾病的遗传复杂性和临床病理特征。将人类细胞移植到小鼠体内经常用于研究人类癌症的生物学，并在体内测试新的抗癌疗法的疗效。但它的价值是有限的，因为科学家目前主要限于侵袭性生长的原发肿瘤或细胞系，这些肿瘤或细胞系不太容易受到异种排斥的影响，对微环境提供的关键信号的依赖程度也较低。因此，开发可靠地在小鼠体内培养原代人类肿瘤细胞的方法是一个尚未得到满足的需求。在这里提出的项目中，微环境的人性化将通过替换和控制小鼠基因组中基本的、但不是交叉反应的生长和生存因子与人类对应的因子来实现。此外，减少髓系细胞的异种排斥和在骨髓壁龛中创造空间的新方法完成了拟议的遗传操作。然后，这些新的体内模型将被用于测试和比较作为基准的急性髓系白血病(AML)移植，并建立原发慢性髓系白血病和骨髓增生性肿瘤以及多发性骨髓瘤的模型，在这些疾病中，缺乏真实反映这些疾病的体内模型限制了研究。这些模型的成功建立将允许对生物学的详细研究，以及对批准的和实验性的治疗方法的验证。开发一个通用的平台，允许在转基因小鼠体内研究人类原发恶性肿瘤，将代表着该领域的重大进展。总而言之，该模型将作为临床前治疗测试的平台，具有更高的预测价值，并允许对肿瘤动态演变的生物学研究对临床实践产生直接影响。 公共卫生相关性：迫切需要新的和创新的疗法来降低癌症的死亡率，但在白血病和淋巴瘤等许多血液癌症的当前研究中，一个基本缺失的环节是在自然环境中研究原始人类肿瘤细胞的能力，我们称之为微环境。我们建议开发一个通用的平台，通过培育提供与人体相似的微环境的小鼠，来进行体内人类癌症的研究。这一模式将作为抗癌药物临床前测试的平台，更有可能使这些药物在人体内发挥作用。

The ultimate interest of biomedical research is the study of humans and the goal is the improvement of human health. However, research on humans is severely compromised by the inability to perform invasive experimental work in order to establish the cause and effect relationships between processes. Mouse models play an important role in characterizing key aspects of the driving forces of malignant transformation and disease in humans. However, they rarely represent the genetic complexity and clinicopathologic characteristics of human disease. Xenotransplantation of human cells into mice is regularly used to study the biology of human cancer and test the efficacy of novel anti-cancer therapies in vivo. But its value is limited because scientists are currently mainly limited to aggressively growing primary tumors or cell lines that are less susceptible to xenorejection and less dependent on critical signals provided by the microenvironment. Therefore there is an unmet need to develop methods to reliably grow primary human tumor cells in mice. In the here proposed project, humanization of the microenvironment will be achieved by replacement and controlled expression of essential, but not cross-reactive, growth and survival factors in the mouse genome with their human counterparts. Furthermore, novel approaches to reduce xenorejection by myeloid cells and to generate space in the bone marrow niche complete the proposed genetic manipulations. These novel in vivo models will then be used to test and compare as a benchmark acute myeloid leukemia (AML) engraftment, and to establish models for primary chronic myeloid leukemia and myeloproliferative neoplasias, as well as multiple myeloma - diseases in which the lack of in vivo models faithfully reflecting these diseases curtails research. Successful establishment of these models would allow detailed studies of biology as well as validation of approved and experimental therapies. The development of a versatile platform allowing the study of human primary malignancies in vivo in genetically modified mice would represent a major advance for the field. In summary, this model will serve as platform for preclinical therapy testing with increased predictive value and allow studies on biology of the dynamic evolution of neoplasias with an immediate impact on clinical practice. PUBLIC HEALTH RELEVANCE: Novel and innovative therapeutics are urgently needed to decrease mortality in cancer, but a fundamental missing link in current research in many blood cancers like leukemias and lymphomas, is the ability to study primary human tumor cells in their natural setting, which we call a microenvironment. We propose to develop a versatile platform that allows the study of human cancers in vivo by generating mice which provide a microenvironment like the one in the human body. This model will serve as a platform for preclinical testing of medicines against cancer with a better likelihood of how well these medicines will work in people.