骨髓间充质干祖细胞通过Spp1／骨桥蛋白途径调控白血病细胞增殖作用及机制研究

Chemotherapy and bone marrow (BM) transplantation are the major therapies for acute myeloid leukemia (AML). Although most of the leukemic cells respond to the initial treatment, drug resistance and relapse are still common. Therefore, alternative treatment targeting BM mesenchymal stem and progenitor cells has drawn increasing attention from clinicians and scientists. We have previously confirmed that BM mesenchymal stem and progenitor cells play critical roles in myeloid malignancies by using different leukemic mouse models. Recently, we have found that the expression of Spp1 gene, coding for osteopontin, significantly increased in the mesenchymal stem and progenitor cells from the AML mice than that from normal controls. Notably, the overexpression of Spp1 by the BM mesenchymal stem and progenitor cells of the AML mice happened before the increased numbers of BM mesenchymal stem and progenitor cells and before the initiation of AML. We here hypothesize that BM mesenchymal stem and progenitor cells may regulate the AML cell proliferation through the overexpression of Spp1/osteopontin. To test this, we plan to conditionally knock out Spp1 from BM mesenchymal stem and progenitors by using transgenic mouse models. We will further phenotypically, functionally, and molecularly analyze the Spp1-/- BM mesenchymal stem and progenitor cells and leukemic cells from the AML mice. The present project will provide important information about the downstream signal pathways of Spp1/osteopontin in both BM mesenchymal stem and progenitor cells and leukemic cells, which will be essential for designing novel therapies targeting on BM mesenchymal stem and progenitor cells for AML treatments.

药物化疗和骨髓移植是目前急性髓系白血病（AML）的主要治疗方案，但难治、复发和耐药仍是影响其预后和长期生存的主要因素。为了寻求新的治疗靶点，骨髓间充质干祖细胞已成为了生物学领域的研究热点。我们前期团队通过多种白血病小鼠模型进行体内研究发现，骨髓间充质干祖细胞对白血病的发生和发展起着关键的调控作用。近来，我们发现编码骨桥蛋白的Spp1基因在AML小鼠的骨髓间充质干祖细胞中表达量明显升高，这种改变早于骨髓间充质干祖细胞数目的增加，且早于AML小鼠发病。因此，我们推测骨髓间充质干祖细胞可能通过Spp1/骨桥蛋白途径调控AML细胞的增殖。本项目拟通过我们前期研究建立的AML小鼠模型，并利用转基因小鼠条件性地在骨髓间充质干祖细胞中敲除Spp1表达，从而深入地研究并阐述骨髓间充质干祖细胞通过表达Spp1/骨桥蛋白调控AML发病的作用机制和信号通路，为寻求新的治疗靶点及靶向药物的临床应用提供理论依据。

化疗、骨髓移植和药物靶向治疗是目前急性髓系白血病（AML）的主要治疗方案。我们通过白血病小鼠模型进行体内研究发现，骨髓间充质干祖细胞对白血病的发生和发展起着关键的调控作用。首先，我们发现编码骨桥蛋白的Spp1基因在AML小鼠的骨髓间充质干祖细胞中表达量明显升高，同时我们发现AML患者骨髓中SPP1骨桥蛋白表达量增高，提示我们建立的AML小鼠模型与AML患者骨髓具有一致性。接下来，我们发现骨髓间充质干祖细胞可能通过Spp1/骨桥蛋白途径抑制AML细胞的凋亡，当敲除骨髓间充质干细胞中的Spp1骨桥蛋白后，通过激活caspase凋亡家族诱导AML细胞凋亡，从而一定程度上了解骨髓间充质干祖细胞通过表达Spp1/骨桥蛋白调控AML发病的可能作用机制和信号通路，为寻求靶向药物的临床应用提供理论依据。