Adhesion GPCR regulation of acute myeloid leukemia stem cells - Resubmission - 1

急性髓系白血病干细胞的粘附 GPCR 调节 - 重新提交 - 1

基本信息

批准号：
10211328
负责人：
CHRISTOPHER Y PARK
金额：
$ 63.72万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211328
关键词：
Acute Myelocytic Leukemia Adhesions Adult Acute Myeloblastic Leukemia Affinity Aftercare Alternative Splicing Antibodies Antibody Therapy Antigens Binding Biological Assay Biology CD97 gene Cells Cessation of life Clinic Clinical Coupled Data Disease EGF-Like Domain Engineering Epitopes Exhibits Extracellular Domain G-Protein-Coupled Receptors Genetic Goals Growth Hematopoietic Hematopoietic stem cells Human In Vitro Ligand Binding Ligand Binding Domain Ligands Maintenance Malignant Neoplasms Mammalian Cell Mediating Molecular Molecular Probes Molecular Structure Mus N-terminal Outcome Pathogenesis Phenotype Physiological Play Population Positioning Attribute Pre-Clinical Model Property Protein Engineering Protein Isoforms Publishing RNA analysis Reagent Regulation Relapse Research Personnel Resistance Role Signal Transduction Solid Specificity Structure Testing Therapeutic Toxic effect Translating Translations Transplantation Undifferentiated Variant Xenograft Model acute myeloid leukemia cell antibody engineering antileukemic activity base chemotherapy curative treatments design experimental study extracellular in vivo in vivo Model insight leukemia leukemia treatment leukemic stem cell leukemic transformation leukemogenesis mRNA Expression member migration mouse model novel phosphoproteomics prognostic receptor structure function screening self-renewal stem cell biology stem cell function stem cell growth stem cell self renewal synthetic antibodies synthetic protein targeted treatment therapeutic target therapy development therapy resistant tool transcriptome sequencing transcriptomics

项目摘要

Despite advances in our understanding of the genetic origins of AML, treatment options have remained essentially unchanged for 30 years, and clinical outcomes remain poor. Leukemia stem cells (LSCs) represent the population of blasts that are resistant to chemotherapy and re-initiate AML after therapy; thus, this subset of blasts must be eradicated to cure disease. Unfortunately, therapies developed specifically to target LSCs have yet to be validated in the clinic. We and others recently identified a novel AML antigen, CD97, that is expressed in the vast majority of human AMLs. Our recently published studies have revealed several features of CD97 that suggest that it may be an excellent therapeutic target in AML: 1) CD97 is one of the most commonly expressed AML antigens; 2) CD97 regulates blast growth, survival, and differentiation; 3) CD97 regulates LSC function, as demonstrated in serial transplantation experiments of primary AML; and, 4) CD97 is not required for HSC function, suggesting low toxicity of CD97-targeting therapeutics. Highlighting its clinical importance, CD97 mRNA expression is an independent predictor of disease-free and overall survival in AML. CD97 is an adhesion class G-protein coupled receptor (aGPCR) characterized by a long, extracellular ligand- binding domain and a GPCR-Autoproteolysis-INducing (GAIN) domain that can induce signals that may or may not require extracellular domain shedding. Isoforms of CD97 produced by alternative splicing differ in the composition of the ligand-binding domain, but at present, it is unclear if the various CD97 isoforms mediate unique or overlapping roles in AML. Our overall hypothesis is that the various CD97 isoforms play distinct roles in leukemogenesis and LSC self-renewal by virtue of their unique ligand binding and/or signaling properties. Our specific goals are to determine the role of CD97 isoforms in leukemic transformation and LSC function, to identify the molecular and structural requirements for CD97 activity, and to utilize novel human synthetic antibodies (sAbs) against CD97 with different epitope specificities to evaluate the function of CD97 as well as test their anti-leukemic activity. We will determine the roles of the various structural subdomains of CD97 required for LSC function utilizing our novel CD97 Abs, CD97 constructs expressing multiple naturally occurring and engineered structural variants of CD97, and complementary in vitro and in vivo models of mouse and human AML. Given our team's complementary expertise in LSC biology, antibody engineering, and aGPCR biology, we are uniquely positioned to investigate the mechanisms of CD97 signaling and function in LSCs. Collectively, these studies will dramatically increase our understanding of the molecular mechanisms that regulate LSC self- renewal and help expedite translation of CD97 antibody therapies to the clinic. Finally, these studies may have broader consequences since CD97 plays disease-modifying roles in other human cancers.

尽管我们对 AML 遗传起源的理解取得了进展，但治疗方案仍然存在 30年来基本没有变化，临床结果仍然很差。白血病干细胞（LSC）代表对化疗有抵抗力并在治疗后重新启动 AML 的原始细胞群体；因此，这个子集必须消灭稻瘟病才能治愈疾病。不幸的是，专门针对 LSC 开发的疗法已经尚待临床验证。我们和其他人最近发现了一种新的 AML 抗原，CD97，它表达存在于绝大多数人类 AML 中。我们最近发表的研究揭示了 CD97 的几个特征：表明它可能是 AML 的一个极好的治疗靶点：1) CD97 是最常表达的基因之一急性髓系白血病抗原； 2）CD97调节胚细胞的生长、存活和分化； 3) CD97调节LSC功能，如在原发性 AML 的系列移植实验中得到证实；并且，4) HSC 不需要 CD97 功能，表明 CD97 靶向疗法的毒性较低。 CD97 mRNA 强调其临床重要性表达是 AML 无病生存和总生存的独立预测因子。 CD97 是一种粘附类 G 蛋白偶联受体 (aGPCR)，其特征是长的细胞外配体结合域和 GPCR 自蛋白水解诱导 (GAIN) 域，可以诱导可能或可能的信号不需要细胞外结构域脱落。通过选择性剪接产生的 CD97 亚型的不同之处在于配体结合结构域的组成，但目前尚不清楚各种 CD97 亚型是否介导 AML 中独特或重叠的角色。我们的总体假设是各种 CD97 亚型发挥着不同的作用凭借其独特的配体结合和/或信号传导特性，参与白血病发生和 LSC 自我更新。我们的具体目标是确定 CD97 同工型在白血病转化和 LSC 功能中的作用，以确定 CD97 活性的分子和结构要求，并利用新型人类合成材料具有不同表位特异性的针对 CD97 的抗体 (sAb)，用于评估 CD97 的功能以及测试它们的抗白血病活性。我们将确定所需CD97的各个结构子域的作用利用我们的新型 CD97 Abs 实现 LSC 功能，CD97 构建体表达多种天然存在和 CD97 的工程结构变体，以及小鼠和人类的互补体外和体内模型反洗钱。鉴于我们团队在 LSC 生物学、抗体工程和 aGPCR 生物学方面的互补专业知识，我们具有独特的优势来研究 LSC 中 CD97 信号传导和功能的机制。总的来说，这些研究将极大地增加我们对调节 LSC 自我调节的分子机制的理解。更新并帮助加快 CD97 抗体疗法转化为临床。最后，这些研究可能由于 CD97 在其他人类癌症中发挥着缓解疾病的作用，因此产生了更广泛的后果。