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

• 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
• 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

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遗传起源的理解有所进步，但治疗方案仍然存在 本质上没有变化30年，临床结果仍然很差。白血病干细胞（LSC）代表 治疗后对化学疗法和重新启动AML有抵抗力的爆炸群体；因此，这个子集 必须将爆炸根除在治愈疾病中。不幸的是，专门针对LSC开发的疗法具有 尚待在诊所进行验证。我们和其他人最近确定了一种新颖的AML抗原CD97 在绝大多数人的AML中。我们最近发表的研究揭示了CD97的几个特征 建议它可能是AML中的出色治疗靶点：1）CD97是最常见的靶标之一 AML抗原； 2）CD97调节爆炸生长，生存和分化； 3）CD97调节LSC功能，为 在初级AML的串行移植实验中证明；而且，4）HSC不需要CD97 功能，表明CD97靶向治疗剂的毒性低。强调其临床重要性，CD97 mRNA 表达是AML中无疾病和总生存期的独立预测指标。 CD97是一种粘附类G蛋白偶联受体（AGPCR），其特征是长长的细胞外配体 结合结构域和GPCR-蛋白酶解诱导（增益）域，该结构域可能会诱导可能或可能可能诱导的信号 不需要细胞外域脱落。替代剪接产生的CD97的同工型在 配体结合域的组成，但目前尚不清楚各种CD97同工型是否介导 AML中的独特或重叠角色。我们的总体假设是，各种CD97同工型都起着不同的作用 在白血病和LSC自我更新中，由于其独特的配体结合和/或信号传导特性。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， 确定CD97活性的分子和结构要求，并利用新型的人类合成 针对具有不同表位特异性的CD97的抗体（SABS），以评估CD97的功能以及 测试他们的抗白血病活性。我们将确定所需CD97各种结构子域的作用 对于利用我们的新型CD97 ABS的LSC功能，CD97构建体表达了多种天然发生的和 CD97的工程结构变体，以及小鼠和人的体外和体内互补的变体 AML。 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 独特地定位了LSC中CD97信号传导和功能的机制。共同 这些研究将大大增加我们对调节LSC自我的分子机制的理解 更新并有助于将CD97抗体疗法加快转换为诊所。最后，这些研究可能有 更广泛的后果，因为CD97在其他人类癌症中扮演了疾病改良的作用。