Regulation of hematopoiesis and leukemogenesis through the hematopoietic stem cell niche in chronic lymphocytic leukemia

通过慢性淋巴细胞白血病的造血干细胞生态位调节造血和白血病发生

• 批准号: 283597560
• 负责人: Dr. Maher Hanoun
• 金额: --
• 依托单位: Klinik für Hämatologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/283597560?language=en
• 关键词: Regulation; hematopoiesis; leukemogenesis; through; hematopoietic

Chronic lymphocytic leukemia (CLL) is the most common leukemia in western countries. Despite advances in anti-leukemic therapy CLL remains incurable if not submitted to allogeneic bone marrow transplantation. Progressed disease is characterized by hematopoietic failure. The hematopoietic balance depends on the integrity of hematopoietic stem cells which is maintained through a tight regulation through the bone marrow niche. The architecture of the bone marrow niche is based on a complex arrangement of cellular and non-cellular constituents, where mesenchymal stem cells form a key player whose function is tightly regulated through the sympathetic nervous system. The aim of this research proposal is to explore to what extent hematopoietic failure can be referred to alterations to the hematopoietic stem cell niche and if lymphatic leukemic cells depend on the same microenvironmental cues like hematopoietic stem cells. In a model of acute myeloid leukemia we have recently shown how malignancies coopt the microenvironment to its own advantage. Leukemic infiltration was shown to induce a local sympathetic neuropathy, disrupting the quiescence of the niche and leading to an accumulation of osteoblast-primed mesenchymal stem cells which finally reinforces malignancy. In a TCL1 mouse model, with striking similarities to human CLL disease, preliminary data reveal alterations in the hematopoietic stem cell and niche regulating capacity of mesenchymal stem cells. At low leukemic burden mesenchymal stem cells already show a defect in the retention of hematopoietic stem and progenitor cells which results in an early mobilization. With increasing leukemic infiltration the hematopoietic stem cell regulating capacity of mesenchymal stem cells is impaired as well as their niche regulating properties are altered. In this research proposal we will dissect the architecture of the CLL bone marrow niche, assess its capacity to regulate healthy and malignant hematopoiesis and elucidate to what extent the observed niche alterations are reversible upon anti-leukemic treatment. These results will be finally validated in human CLL disease. These new insights will open therapeutic targets to restore healthy hematopoiesis and eradicate leukemic disease in its niche.

慢性淋巴细胞白血病(CLL)是西方国家最常见的白血病。尽管抗白血病治疗取得了进展，但如果不接受异基因骨髓移植，慢性淋巴细胞性白血病仍然是无法治愈的。进展性疾病的特征是造血功能衰竭。造血平衡依赖于造血干细胞的完整性，而造血干细胞的完整性是通过骨髓缝隙的严密调节来维持的。骨髓生态位的结构是基于细胞和非细胞成分的复杂排列，其中间充质干细胞形成了一个关键角色，其功能受到交感神经系统的严格调控。这项研究计划的目的是探索造血衰竭在多大程度上可以归因于造血干细胞生态位的改变，以及淋巴性白血病细胞是否依赖于相同的微环境信号，如造血干细胞。在一个急性髓系白血病的模型中，我们最近展示了恶性肿瘤是如何利用微环境来获得自身优势的。白血病的侵袭被证明引起局部的交感神经病变，扰乱了壁龛的平静，导致成骨细胞启动的间充质干细胞的积聚，最终加剧了恶性肿瘤。在与人类CLL疾病惊人相似的TCL1小鼠模型中，初步数据显示造血干细胞和间充质干细胞的生态位调节能力发生了变化。在白血病负荷较低的情况下，间充质干细胞在造血干细胞和造血祖细胞的保留方面已经表现出缺陷，这导致了早期动员。随着白血病浸润率的增加，间充质干细胞的造血干细胞调节能力受损，其生态位调节特性也发生改变。在这项研究方案中，我们将剖析CLL骨髓生态位的结构，评估其调节健康和恶性造血的能力，并阐明所观察到的生态位变化在抗白血病治疗中的可逆性程度。这些结果将最终在人类CLL疾病中得到验证。这些新的见解将为恢复健康的造血和根除其利基领域的白血病疾病打开治疗靶点。