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: 10579217
• 负责人: CHRISTOPHER Y PARK
• 金额: $ 58.93万
• 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/10579217
• 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; Mus; N-terminal; Outcome; Pathogenesis; Phenotype; Physiological; Play; Population; Positioning Attribute; Pre-Clinical Model; Property; Protein Engineering; Protein Isoforms; Publishing; Reagent; Regulation; Relapse; Research Personnel; Resistance; Role; Signal Induction; Signal Transduction; Solid; Specificity; Testing; Therapeutic; Toxic effect; Translating; Translations; Transplantation; Undifferentiated; Variant; Xenograft Model; acute myeloid leukemia cell; antibody engineering; antileukemic activity; chemotherapy; curative treatments; design; experimental study; extracellular; in vivo; in vivo Model; insight; leukemia; 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.

Despite advances in our understanding of the genetic origins of AML, treatment options have remained 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。 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 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 demonstrated in serial transplantation experiments of primary AML;并且，4) HSC 不需要 CD97 function, suggesting low toxicity of CD97-targeting therapeutics. CD97 mRNA 强调其临床重要性 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 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。 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.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 identify the molecular and structural requirements for CD97 activity, and to utilize novel human synthetic 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。 We will determine the roles of the various structural subdomains of CD97 required 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 engineered structural variants of CD97, and complementary in vitro and in vivo models of mouse and human 反洗钱。 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.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。 renewal and help expedite translation of CD97 antibody therapies to the clinic.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。