Therapeutic Targeting of Leukemia-Microenvironmental Interactions

白血病-微环境相互作用的治疗靶向

基本信息

批准号：
9228955
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-11 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228955
关键词：
Acute Acute Myelocytic Leukemia Age Area Blood Cells Bone Marrow Bone Marrow Diseases CCL3 gene CCR1 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 Forteo Gender Genetic Goals Hematopoiesis Hematopoietic Hematopoietic stem cells Hemorrhage Human Impairment 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 Pharmacology Phenotype Production Recovery Regulation Relapse Research Risk Role Sampling Signal Transduction Supporting Cell Transfusion Translations bone chemokine disorder control improved in vivo Model intravital microscopy leukemia leukemic stem cell loss of function mortality mouse model novel overexpression public health relevance receptor response therapeutic target tool volunteer

项目摘要

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）：对白血病克隆抑制正常造血的机制知之甚少，但这种现象可能会导致疾病进展、疾病发病率和对治疗的反应。我们最近对同基因小鼠急性髓系白血病模型的骨髓微环境（BME）进行的分析表明存在显着的成骨细胞缺陷。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正常 HSC 恢复并减少白血病干细胞 (LSC) 的 BME 支持的潜在临床靶点）。此外，我们发现了趋化因子 CCL3 的白血病产生，最近被证明可以抑制多发性骨髓瘤中的成骨细胞功能。当前提案的长期目标是针对 HSC 和白血病干细胞 (LSC) 生态位，改善白血病治疗并影响疾病控制，旨在高效、有效和安全地应用药理学工具目前被批准用于白血病的骨合成代谢治疗。我们假设 1) 白血病细胞减少 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) 干扰白血病信号，破坏骨合成代谢治疗的 ME 和/或 ME 刺激白血病的减少将改善 HSC 支持并降低 LSC 竞争力。使用两种小鼠模型以及一种从正常和白血病人骨髓样本中的针状体中分离成骨细胞的新方法，我们建议：1.)定义白血病诱导的成骨细胞谱系抑制的程度和时间。 2.) 定义白血病诱导的 ME 支持正常和恶性造血能力的变化。 3.) 使用功能丧失、过度表达和药理学方法确定 CCL3 作为白血病诱导的 ME 变化介质的要求。 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。该项目的数据将代表 AML 患者治疗的范式转变，其中靶向 BME 提高了我们治疗白血病的能力，并更容易恢复正常造血功能。刺激骨形成细胞的药物已经可供患者在非恶性情况下使用，从而可以快速转化为临床。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

DOI：
10.1371/journal.pone.0132375
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Sivagnanalingam U;Balys M;Eberhardt A;Wang N;Myers JR;Ashton JM;Becker MW;Calvi LM;Mendler JH
通讯作者：
Mendler JH