The leukemic stem cell niche - parallels to its physiological counterpart

造血干细胞存在于特定的小生境中，调节它们在骨髓中的存活、增殖、自我更新或分化。正常干细胞和白血病干细胞之间的相似之处以及它们在特定的生态位内的调节。已经表明，交感神经系统调节骨髓中的造血干细胞及其前体细胞。依赖于骨髓中的肾上腺素能信号，循环中的HSC及其前体细胞表现出强烈的昼夜振荡。此外，在造血干细胞生态位中一个新的关键人物被鉴定为巢蛋白阳性细胞，它的行为被证明类似于间充质干细胞。以前列腺癌为例，新的数据强调了自主神经系统在调节癌症的发生和扩散中的作用。本研究的目的是阐述自主神经系统、昼夜节律和巢蛋白阳性的间充质干细胞在急性髓系白血病发病机制中的作用。我们假设交感神经系统调节白血病的启动和扩展，昼夜节律的破坏会影响白血病克隆的生长，在巢蛋白阳性细胞耗尽后，白血病的发展将受到损害。在这项研究中，我们使用转基因和异种小鼠模型，进行遗传、药理学和外科去神经治疗，并使用最先进的成像技术。目的是比较生理和恶性生态位，并利用差异进行靶向抗肿瘤治疗，选择性地消耗白血病细胞的重新繁殖部分，最终克服其耐药性。

Hematopoietic stem cells reside in specific niches that regulate their survival, proliferation, selfrenewal or differentiation in the bone marrow. Parallels between normal stem cells and leukemia stem cells and their regulation within specific niches have been suggested.It has been shown that the sympathetic nervous system regulates hematopoietic stem cells and their progenitors in the bone marrow. Depending on the adrenergic signaling within the bone marrow circulating HSCs and their progenitors exhibit robust circadian oscillations. Moreover, a novel key figure in the hematopoietic stem cell niche has been identified as nestin-positive cells, which proved to behave like mesenchymal stem cells. Emerging data have highlighted the role of the autonomous nervous system in regulation of cancer initiation and dissemination using the example of prostate cancer.The purpose of this study is to elaborate the role of the autonomous nervous system, the circadian rhythm and nestin-positive mesenchymal stem cells in the pathogenesis of acute myeloid leukemia. We hypothesize that the sympathetic nervous system regulates leukemia initiation and expansion, disruption of the circadian rhythm influences growth of the leukemic clone and after depletion of nestin-positive cells leukemia development is going to be impaired.In this study we are working with transgenic and xenogeneic mouse models, performing genetic, pharmacological and surgical denervation and using state-of-the-art imaging.The aim is to compare the physiological and malignant niche and use differences for targeted antineoplastic therapies to selectively deplete the repopulating fraction of leukemia cells and eventually overcome their drug resistance.