Membrane protein target for leukemia therapy

白血病治疗的膜蛋白靶点

基本信息

批准号：
10674030
负责人：
Xunlei Kang
金额：
$ 45.4万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674030
关键词：
3-Dimensional AML1-ETO fusion protein Acute Myelocytic Leukemia Address Age Apoptosis Binding Biological Assay Bone Marrow Cell Communication Cell Surface Proteins Cell Transplantation Cell surface Clinical Colony-Forming Units Assay Colony-forming units Complete Blood Count Data Databases Development Diagnosis Dipeptidyl Peptidases Disease Engraftment Exhibits Extracellular Fluid Feedback Gene Expression Goals Growth Hematologic Neoplasms Human In Vitro Investigation Knock-out MLL-AF9 Malignant Neoplasms Mediating Medicine Membrane Proteins Methods Molecular Mus Myelosuppression NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Patients Peripheral Persons Play Proteins Regulation Research Role Serum Signal Transduction Stromal Cells Survival Rate Testing Treatment Protocols Tumor Burden United States Xenograft Model Xenograft procedure acute myeloid leukemia cell cancer stem cell cancer therapy cell growth chemotherapy comorbidity cytokine high resolution imaging imaging study improved improved outcome in silico in vivo inhibitor knock-down leukemia leukemia treatment leukemic stem cell migration mortality mouse model novel novel strategies p65 prevent progenitor restoration restraint self-renewal small hairpin RNA src-Family Kinases standard care therapy development trafficking transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) accounts for more than 40% of leukemia mortality in the United States. Each year around ten thousand people die from the disease, most within a few years of diagnosis. Despite advances in our understanding of the disease, few improvements in the therapy of AML have been made. Specific targets and novel strategies to eliminate AML stem cells are required for AML treatment. In preliminary studies, the PI’s lab has observed the following: 1) The expression of DPP4 negatively correlates with AML patient overall survival in 3 different databases. 2) DPP4 inhibitors can prevent AML development in vivo. 3) DPP4 inhibitors can prevent both human and mouse AML cells growth in vitro. 4) DPP4 knock out (KO) AML cells transplanted mice exhibit delay and reversal of AML development in two retroviral-induced AML mouse models. 5) DPP4 KO AML stem cells and progenitors (AML-SCP) are restrained in the bone marrow, with increased apoptosis, and reduced self-renewal ability. 6) DPP4 knockdown prevents the growth of human AML cells. 7) The activation of Src, IkB, and p65 is reduced in DPP4 KO AML cells. Based on these preliminary data, the central hypothesis is: DPP4 regulated trafficking, activation and apoptosis of AML-SCPs are critical for human AML development, which will be addressed in three specific aims. Aim 1: Determine the role of DPP4 in human AML development. The localization, apoptosis, and self-renewal of DPP4 deficient human AML-SCP will be investigated by colony forming unit assay and human AML cells xenografted mouse model. Using the xenograft model, the effect of DPP4 inhibitors treatment alone or in combination with standard chemotherapy to prevent AML development will be evaluated. Aim 2: Examine regulation of AML- SCP engraftment to the BM by DPP4. This will include identification of the critical cytokines regulated by DPP4 for AML-SCP trafficking. To test this, the PI will use migration and engraftment assays. In addition, the PI will investigate localization and niche cells interaction of DPP4 KO AML-SCPs in the BM microenvironment by imaging studies. Aim3: Investigate the role of DPP4 in AML-SCP survival. We will explore the critical domain of DPP4, if DPP4-Src interaction is essential for AML-SCP survival, how DPP4 regulates the activity and protein level of Src in AML-SCP and determine if dual therapy with DPP4 and Src inhibitors has greater benefits against human AML-SCP survival. Collectively, the proposed research will broadly impact the field by identification of a novel treatment for AML, via the strategy of confinement of AML-SCP to bone marrow, and improving the understanding of the role of microenvironment in the development of AML-SCPs.

项目概要/摘要在美国，急性髓系白血病 (AML) 占白血病死亡率的 40% 以上。每年约有万人死于这种疾病，大多数在诊断后几年内死亡。根据我们对这种疾病的了解，AML 的治疗几乎没有取得任何进展。在初步研究中，需要消除 AML 干细胞的目标和新策略。 PI 实验室观察到以下情况： 1) DPP4 阴性表达与 AML 患者相关 3 个不同数据库中的总体生存率 2) DPP4 抑制剂可以预防体内 AML 的发展。抑制剂可以阻止人类和小鼠 AML 细胞在体外生长 4) DPP4 敲除 (KO) AML 细胞。移植小鼠在两只逆转录病毒诱导的 AML 小鼠中表现出 AML 发展的延迟和逆转 5) DPP4 KO AML 干细胞和祖细胞 (AML-SCP) 被限制在骨髓中， 6) DPP4敲除可阻止人类AML的生长 7) 基于这些初步结果，DPP4 KO AML 细胞中 Src、IkB 和 p65 的激活减少。数据，中心假设是：DPP4 调节 AML-SCP 的运输、激活和凋亡对于人类 AML 的发展至关重要，这将通过三个具体目标来解决：确定。 DPP4 在人类 AML 发展中的作用 DPP4 的定位、细胞凋亡和自我更新。缺陷型人类 AML-SCP 将通过集落形成单位测定和人类 AML 细胞异种移植进行研究使用异种移植模型，观察DPP4抑制剂单独或联合治疗的效果。将评估预防 AML 发展的标准化疗。目标 2：检查 AML 的监管。 DPP4 将 SCP 植入到 BM 这将包括鉴定受 DPP4 调节的关键细胞因子。用于 AML-SCP 贩运的 DPP4 为了测试这一点，PI 将使用迁移和植入测定。 PI 将研究 DPP4 KO AML-SCP 在 BM 微环境中的定位和利基细胞相互作用目标 3：研究 DPP4 在 AML-SCP 存活中的作用。 DPP4 的结构域，如果 DPP4-Src 相互作用对于 AML-SCP 生存至关重要，那么 DPP4 如何调节活性和 AML-SCP 中 Src 的蛋白水平，并确定 DPP4 和 Src 抑制剂的双重治疗是否具有更大的效果总的来说，拟议的研究将通过以下方式广泛影响该领域。通过将 AML-SCP 限制在骨髓中的策略，确定了一种新的 AML 治疗方法，以及提高对微环境在 AML-SCP 发展中作用的理解。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Repair of Limb Ischemia Is Dependent on Hematopoietic Stem Cell Specific-SHP-1 Regulation of TGF-β1.

DOI：
10.1161/atvbaha.122.318205
发表时间：
2023-01
期刊：
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
影响因子：
8.7
作者：
Wang, Chen;Nistala, Ravi;Cao, Min;Li, De-Pei;Pan, Yi;Golzy, Mojgan;Cui, Yuqi;Liu, Zhenguo;Kang, XunLei
通讯作者：
Kang, XunLei

Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells.