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）：白血病克隆抑制正常造血的机制知之甚少，但是这种现象可能有助于疾病进展，疾病的发病率和对治疗的反应。我们最近对急性髓样白血病的合成小鼠模型中骨髓微环境（BME）的分析表明，巨大的成骨细胞缺陷。由于我们的实验室和其他实验室已经证明了成骨细胞在造血干细胞（HSC）调节中的核心作用，因此这些数据识别成骨细胞是刺激白血病中正常HSC恢复并减少白血病干细胞（LSCS）BME支持的潜在临床靶标。此外，我们发现了趋化因子CCL3的白血病产生，最近证明可以抑制多发性骨髓瘤的成骨细胞功能。凭借针对HSC和白血病干细胞（LSC）壁ches以改善白血病和影响疾病控制治疗的长期目标，目前的建议旨在有效，有效，有效，安全地应用药理工具目前已批准用于白血病的骨合代疗法。我们假设1）白血病细胞降低了HSC和正常造血对LSC和散装白血病的支持，促进疾病的进展； 2）在白血病治疗中，干扰白血病的干扰会破坏ME和/或ME ME刺激，从而在Leukemia的背景下降低HSC的支持和降低HSC竞争力。使用两种鼠模型以及一种新型的方法，可以从正常和白血病人类骨髓样品中从spicules中分离成骨细胞细胞，我们提出：1。1.）定义白血病诱导的成骨细胞抑制的程度和时间。 2.）定义白血病的变化引起的我支持正常和恶性造血的能力。 3.）确定CCL3作为白血病介体的要求，通过功能，过表达和药理方法的丧失引起了我的变化。 4.）确定白血病相关成骨细胞的治疗靶向是否会影响正常的造血，疾病进展和LSC功能。该项目的数据将代表用于AML患者治疗的范式转移，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。刺激骨形成细胞的药物已经可以在非恶性场景中使用患者使用，从而可以快速转化为诊所。

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