Therapeutic Targeting of Leukemia-Microenvironmental Interactions

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，但这种现象可能导致疾病进展、疾病发病率和对治疗的反应。我们最近对急性髓系白血病的同基因小鼠模型的骨髓微环境（BME）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人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，这些数据确定成骨细胞是刺激白血病患者正常造血干细胞恢复和减少白血病干细胞（LSCs） 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CCL3，最近被证明可以抑制多发性骨髓瘤的成骨细胞功能。长期目标是靶向HSC和白血病干细胞（LSC）利基，以改善白血病治疗和影响疾病控制，目前的建议旨在高效，有效和安全地应用药物工具

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.