Targeting osteoblasts to inhibit AML

靶向成骨细胞抑制 AML

• 批准号: 9058501
• 负责人: KAREN E. HEDIN
• 金额: $ 17.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-23 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058501
• 关键词: Acute Myelocytic Leukemia; Aftercare; Alkaline Phosphatase; Animals; Apoptosis; Ara-C; BCL2 gene; Biological Assay; Bone Marrow; Bone Surface; CXCL12 gene; CXCR4 gene; Cell Line; Cell Survival; Cell model; Cells; Cessation of life; Coculture Techniques; Cyclosporine; Data; Development; Disease; Disease remission; Family member; Goals; HDAC3 gene; Health; In Vitro; Knock-out; Life; Ligands; MLL-AF9; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Mus; Mutation; Osteoblasts; Osteocytes; Patients; Reagent; Relapse; Resistance; Sampling; Severities; Severity of illness; Staging; Stem cells; Stromal Cell-Derived Factor 1; Survival Rate; System; Testing; Tissues; cancer cell; cell type; chemokine receptor; chemotherapy; design; improved; in vivo; killings; knock-down; mouse model; novel therapeutics; osteoblast differentiation; osteoprogenitor cell; prevent; response; therapeutic development; transcription factor

 DESCRIPTION (provided by applicant): New therapies are urgently needed for Acute Myelogenous Leukemia (AML). Treatment-resistant AML cells are evidently protected within bone marrow endosteal niches. This proposal is designed to provide groundwork for the development of new therapies aimed at inhibiting the cellular mechanisms of the bone marrow microenvironment that protect AML cells. We recently found that differentiating osteoblasts, but not the osteoprogenitors or terminally-differentiated osteocytes, are capable of protecting AML cells from apoptosis including that induced by SDF-1 (CXCL12) secreted by other cells in the bone marrow microenvironment. Additionally, our preliminary data indicates that differentiating osteoblasts also protect AML cells from chemotherapeutic-induced apoptosis. Interestingly, our results indicate that an early stage of differentiation of osteoprogenitors towards osteoblasts is crucial to permit these cells to protect AML cells. Inhibition of the specific stage(s) of osteoblat differentiation capable of protecting AML cells from SDF-1- or chemotherapeutic-induced apoptosis might enhance the efficacy of current therapies of AML. Unfortunately, this "protective" stage of osteoblast differentiation is not clearly defined at present. Here, we propos to use our in vitro co-culture systems and mouse models of AML to test our hypothesis that inhibiting osteoblast differentiation will significantly impair the ability of the endosteal bone marrow niche to protect AML cells. Our Aims are to 1) Disrupt specific stages of osteoblast differentiation via characterized genetic alterations in order to identify the particular stage(s) f osteoblast development capable of protecting AML cells in in vitro co-culture models of the bone marrow, and to 2) Determine the survival rate and localization of AML cells in mouse bone marrow microenvironments deficient in osteoblast differentiation, and assess the effects on the severity of AML disease and the rate of relapse in these animals. Combined, these studies will test our hypothesis and identify the particular stage(s) of osteoblast differentiation that mediate protection of AML cells from SDF-1- and chemotherapeutic-induced apoptosis.

 描述（由申请人提供）：急性髓性白血病（AML）迫切需要新疗法。治疗耐药的 AML 细胞显然在骨髓内膜微环境中受到保护。该提案旨在为开发新疗法奠定基础，旨在抑制保护 AML 细胞的骨髓微环境的细胞机制。我们最近发现，分化的成骨细胞，而不是骨祖细胞或终末分化的骨细胞，能够保护 AML 细胞免于凋亡，包括由骨髓微环境中其他细胞分泌的 SDF-1 (CXCL12) 诱导的凋亡。此外，我们的初步数据表明，分化的成骨细胞还可以保护 AML 细胞免受化疗诱导的细胞凋亡。有趣的是，我们的结果表明，骨祖细胞向成骨细胞分化的早期阶段对于这些细胞保护 AML 细胞至关重要。抑制成骨细胞分化的特定阶段能够保护 AML 细胞免受 SDF-1 或化疗诱导的细胞凋亡，可能会增强当前 AML 疗法的功效。不幸的是，目前成骨细胞分化的这种“保护性”阶段尚未明确定义。在这里，我们建议使用体外共培养系统和 AML 小鼠模型来检验我们的假设，即抑制成骨细胞分化将显着损害骨内骨髓微环境保护 AML 细胞的能力。我们的目标是 1) 通过特征性遗传改变破坏成骨细胞分化的特定阶段，以确定能够在骨髓体外共培养模型中保护 AML 细胞的成骨细胞发育的特定阶段，以及 2) 确定 AML 细胞在成骨细胞分化缺陷的小鼠骨髓微环境中的存活率和定位，并评估其对成骨细胞分化严重程度的影响 这些动物的 AML 疾病和复发率。结合起来，这些研究将检验我们的假设，并确定成骨细胞分化的特定阶段，该阶段介导保护 AML 细胞免受 SDF-1 和化疗诱导的细胞凋亡。