Understanding the niche of minimal residual disease leukemia cells

了解微小残留病白血病细胞的生态位

基本信息

批准号：
10226951
负责人：
Yong-Mi Kim Kim
金额：
$ 40.26万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
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：
2013-08-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226951
关键词：
Acute Lymphocytic Leukemia Address Adhesions Adult Acute Lymphocytic Leukemia Affect Antibodies Apoptosis B-cell precursor acute lymphoblastic leukemia cell Blocking Antibodies Bone Marrow Bone Marrow Cells Calvaria Cell Adhesion Molecules Cell Death Cell surface Cells Characteristics Chemoprotective Agent Childhood Combination Drug Therapy Data Detection Disease Marker Drug resistance Extracellular Matrix Flow Cytometry Goals Histocytochemistry Human In Situ In Vitro Integrin Inhibition Integrin alpha6 Interruption Laminin Laminin Receptor Leukemic Cell Link Location Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Modeling Mus Neoplasm Metastasis Outcome Patients Peptides Pharmaceutical Preparations Pharmacotherapy Pre-B Acute Lymphoblastic Leukemia Prognosis Property Proteins Relapse Residual Neoplasm Safety Sampling Signal Transduction Site Testing Therapeutic Time Toxic effect Transplantation Treatment Failure Tyrosine Tysabri Visualization Xenograft Model acute lymphoblastic leukemia cell adhesion receptor cell killing cell motility chemotherapy conditional knockout experimental study imaging modality in vivo insight intravital imaging leukemia leukemia initiating cell leukemia relapse long bone mouse model new therapeutic target non-drug novel pre-clinical prevent protective effect tissue culture transplant model treatment strategy

项目摘要

PROJECT SUMMARY When acute lymphoblastic leukemia (ALL) cells evade the toxicity of cytoreductive chemotherapy, minimal residual disease (MRD) and relapse ensue. MRD remains a major obstacle, which is unaddressed by current therapies. Recently, integrin alpha6 (Itga6) was identified as a novel flow cytometric MRD marker. Why Itga6 marks MRD ALL cells is unknown. We developed novel models to study the emergence of MRD. This novel MRD ALL model enables us to perform in situ characterization of bone marrow (BM) cells neighboring MRD ALL cells and in vivo visualization of interactions of such MRD ALL cells with BM niches in real-time allowing us to study real-time interactions of MRD ALL cells with the BM. Our preliminary data identify Itga6 as a cell surface adhesion receptor for laminin on specific ALL cell subtypes which protects these cells against drug treatment. However, our data also show that Itga6 has a pro-survival function independent of laminin. Moreover, Cre-mediated deletion of Itga6 in murine pre-B ALL cells in vitro reproducibly induces apoptosis. In xenograft model of primary ALL, combination chemotherapy treatment with P5G10, an Itga6-specific Ab, enhanced survival of leukemia bearing mice. As our data show that the functions of Itga6 and another adhesion molecule, Itga4, differ which also is expressed on ALL cells, differ, we will test a novel concept of dual integrin inhibition as treatment strategy for ALL. Preliminary mass spectrometry analysis provides mechanistic correlates of observed Itga6-associated apoptosis which provide the basis for studying the underlying mechanism of how Itga6 promotes survival of ALL cells. Our overall hypothesis and premise for these studies is that MRD pre-B ALL cells are located in a specific niche in the BM, and that Itga6 expression in ALL cells is a critical component that imparts leukemia-initiating cell characteristics, including drug insensitivity, to MRD cells. The following aims will test this hypothesis: Aim 1 will characterize the BM niche cells in contact with MRD ALL cells in situ and in real-time in vivo and in vitro. Aim 2 determines the underlying mechanism of Itga6-promoted MRD ALL survival. Finally, Aim 3 will preclinically evaluate the concept of Itga6 inhibition alone and in combination with Itga4 inhibition to eradicate MRD ALL. Our proposed studies may further establish the proof-of-principle in which interruption of the Itga6/BM interaction abrogates protection of the MRD niche to ALL, changing current concepts of treating ALL to include strategies targeting the MRD niche.

项目概要当急性淋巴细胞白血病（ALL）细胞逃避细胞减灭化疗的毒性时，最小的残留病灶（MRD）和复发随之而来。 MRD 仍然是一个主要障碍，目前尚未解决疗法。最近，整合素α6（Itga6）被鉴定为一种新型流式细胞术MRD标记物。为什么选择Itga6 标记MRD ALL 细胞未知。我们开发了新的模型来研究 MRD 的出现。这部小说 MRD ALL 模型使我们能够对 MRD 附近的骨髓 (BM) 细胞进行原位表征 ALL 细胞以及此类 MRD ALL 细胞与 BM 生态位相互作用的体内可视化实时显示我们研究 MRD ALL 细胞与 BM 的实时相互作用。我们的初步数据将 Itga6 识别为细胞特定 ALL 细胞亚型上层粘连蛋白的表面粘附受体，可保护这些细胞免受药物侵害治疗。然而，我们的数据还表明 Itga6 具有独立于层粘连蛋白的促生存功能。此外，在小鼠 pre-B ALL 细胞中，Cre 介导的 Itga6 缺失在体外可重复诱导细胞凋亡。在原发性 ALL 异种移植模型，采用 P5G10（一种 Itga6 特异性抗体）联合化疗，提高患有白血病的小鼠的存活率。正如我们的数据显示，Itga6 和另一个的功能粘附分子 Itga4 也不同，它也在所有细胞上表达，不同，我们将测试一个新概念双重整合素抑制作为 ALL 的治疗策略。初步质谱分析提供观察到的 Itga6 相关细胞凋亡的机制相关性，为研究 Itga6 如何促进 ALL 细胞存活的潜在机制。我们的总体假设和前提这些研究表明 MRD pre-B ALL 细胞位于 BM 的特定生态位中，并且 Itga6 表达在 ALL 细胞中，它是赋予白血病起始细胞特征的关键成分，包括药物对 MRD 细胞不敏感。以下目标将检验这一假设：目标 1 将描述 BM 利基市场的特征细胞与 MRD ALL 细胞在体内和体外原位实时接触。目标 2 确定基础 Itga6 促进 MRD ALL 存活的机制。最后，Aim 3将对Itga6的概念进行临床前评估单独抑制或与 Itga4 抑制联合使用可根除 MRD ALL。我们提出的研究可能进一步建立原理验证，其中 Itga6/BM 相互作用的中断会取消对 ALL 的 MRD 利基，改变当前治疗 ALL 的概念，包括针对 MRD 的策略利基。