Understanding Hemotopoietic Neoplasias using Humanized Mice

描述（由申请人提供）：生物医学研究的最终兴趣是对人类的研究，目标是改善人类健康。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损害。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，它们很少代表人类疾病的遗传复杂性和临床病理特征。人类细胞异种移植在小鼠体内经常被用于研究人类癌症的生物学和测试新的抗癌疗法的体内疗效。但它的价值是有限的，因为科学家目前主要局限于积极生长的原发肿瘤或细胞系，这些细胞系对异种排斥反应不太敏感，对微环境提供的关键信号的依赖程度也较低。因此，在小鼠体内可靠地培养原代人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必需的，但不是交叉反应的生长和生存因子与人类对应因子的表达来实现。此外，减少骨髓细胞异种排斥反应和在骨髓生态位中产生空间的新方法完成了提出的遗传操作。这些新的体内模型随后将用于测试和比较作为基准的急性髓性白血病（AML）移植，并建立原发性慢性髓性白血病和骨髓增生性肿瘤以及多发性骨髓瘤的模型-缺乏真实反映这些疾病的体内模型限制了这些疾病的研究。这些模型的成功建立将允许对生物学进行详细的研究，并验证已批准的和实验性的治疗方法。开发一种多功能平台，允许在转基因小鼠体内研究人类原发性恶性肿瘤，将代表该领域的重大进步。综上所述，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，并允许对肿瘤动态进化的生物学研究，对临床实践产生直接影响。

DESCRIPTION (provided by applicant): 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.