Therapeutic Targeting of Leukemia-Microenvironmental Interactions

白血病-微环境相互作用的治疗靶向

• 批准号: 8843266
• 负责人: MICHAEL W BECKER
• 金额: $ 31.85万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-11 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843266
• 关键词: Acute; Acute Myelocytic Leukemia; Age; Area; Blood Cells; Bone Marrow; Bone Marrow Diseases; CC chemokine receptor 1; CCL3 gene; CCR5 gene; Cell Communication; Cell Lineage; Cell physiology; Cells; Clinic; Clinical; Coculture Techniques; Data; Defect; Diagnosis; Disease; Disease Management; Disease Progression; Disease remission; Endothelial Cells; Gender; Genetic; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Individual; Infection; Laboratories; MLL-AF9; Macrophage Inflammatory Protein-1; Malignant - descriptor; Marrow; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Multiple Myeloma; Mus; Myelogenous; Non-Malignant; Osteoblasts; Patients; Phenotype; Production; Recovery; Regulation; Relapse; Research; Risk; Role; Sampling; Signal Transduction; Teriparatide; Time; Transfusion; Translations; bone; chemokine; disorder control; improved; in vivo Model; intravital microscopy; leukemia; leukemic stem cell; loss of function; mortality; mouse model; novel; overexpression; response; stem cell niche; therapeutic target; tool; volunteer

DESCRIPTION (provided by applicant): The mechanisms by which a leukemic clone suppresses normal hematopoiesis are poorly understood, and yet this phenomenon likely contributes to disease progression, disease morbidity and response to therapy. Our recent analysis of the bone marrow microenvironment (BME) in a syngeneic mouse model of acute myeloid leukemia1 demonstrated dramatic osteoblastic defects. Since our laboratory and others have demonstrated the central role of osteoblastic lineage cells in hematopoietic stem cell (HSC) regulation, these data identify osteoblastic cells as a potential clinical target to stimulat normal HSC recovery in leukemia and decrease BME support of leukemic stem cells (LSCs). Moreover, we discovered leukemic production of the chemokine CCL3, recently demonstrated to inhibit osteoblastic function in multiple myeloma. With the long-term goal of targeting the HSC and leukemia stem cell (LSC) niches to improve therapy for leukemia and impact disease control, the current proposal aims to efficiently, effectively and safely apply pharmacologic tools currently approved for bone anabolic treatment to leukemia. We hypothesize that 1) leukemia cells decrease the ME support of HSCs and normal hematopoiesis in favor of LSCs and bulk leukemia, promoting disease progression and that 2) interference with leukemia signals disrupting the ME and/or ME stimulation by bone anabolic treatment in the context of leukemia will improve HSC support and decrease LSC competitiveness. Using two murine models as well as a novel method of isolation of osteoblastic cells from spicules in normal and leukemic human bone marrow samples, we propose to: 1.) Define the extent and timing of leukemia-induced osteoblastic lineage inhibition. 2.) Define changes on leukemia-induced ME ability to support normal and malignant hematopoiesis. 3.) Establish the requirement for CCL3 as the mediator of leukemia-induced ME changes using loss of function, overexpression and pharmacologic approaches. 4.) Determine if therapeutic targeting of leukemia-associated osteoblasts impacts normal hematopoiesis, disease progression and LSC function. Data from this project would represent a paradigm shift in the therapy for patients with AML, where targeting of the BME improves our ability to treat the leukemia and more readily restore normal hematopoiesis. Agents stimulating bone forming cells are already available for patient use in the non-malignant scenario allowing for rapid translation into the clinic.

描述（由申请人提供）：白血病克隆抑制正常造血的机制尚不清楚，但这种现象可能有助于疾病进展、疾病发病率和治疗反应。我们最近对急性髓性白血病同基因小鼠模型的骨髓微环境（BME）的分析显示了显著的成骨细胞缺陷。由于我们的实验室和其他实验室已经证明了成骨细胞谱系细胞在造血干细胞（HSC）调节中的核心作用，这些数据将成骨细胞确定为刺激白血病中正常HSC恢复和减少白血病干细胞（LSC）的BME支持的潜在临床靶点。此外，我们发现白血病产生的趋化因子CCL 3，最近证明抑制成骨细胞功能的多发性骨髓瘤。长期目标是靶向HSC和白血病干细胞（LSC）小生境，以改善白血病治疗并影响疾病控制，目前的提案旨在高效、有效和安全地应用药理学工具 目前被批准用于治疗白血病的骨合成代谢。我们假设：1）白血病细胞降低了HSC和正常造血的ME支持，有利于LSC和大量白血病，促进疾病进展，2）在白血病背景下，通过骨合成代谢治疗干扰白血病信号破坏ME和/或ME刺激，将改善HSC支持并降低LSC竞争力。使用两种小鼠模型以及从正常和白血病人骨髓样品中的骨针分离成骨细胞的新方法，我们提出：1。确定白血病诱导的成骨细胞谱系抑制的程度和时间。2.）的情况。定义白血病诱导的ME支持正常和恶性造血能力的变化。3.）第三章使用功能丧失、过表达和药理学方法确定CCL 3作为白血病诱导ME变化的介质的要求。4.）确定白血病相关成骨细胞的治疗靶向是否影响正常造血、疾病进展和LSC功能。来自该项目的数据将代表AML患者治疗的范式转变，其中BME的靶向提高了我们治疗白血病的能力，并且更容易恢复正常的造血。刺激骨形成细胞的试剂已经可用于非恶性情况下的患者使用，从而允许快速转化为临床。