Therapeutic targeting of MDS stem cells

MDS 干细胞的治疗靶向

• 批准号: 9982095
• 负责人: Ulrich Steidl
• 金额: $ 52.89万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982095
• 关键词: Antibodies; Automobile Driving; Azacitidine; Biological; CD34 gene; Cell Fraction; Cell Line; Cells; Clinical; Data; Dependence; Disease; Disease Progression; Disease remission; Dysmyelopoietic Syndromes; Dysplasia; Enhancers; Genetic; Genetic Transcription; Growth; Hematological Disease; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; IL8 gene; IL8RB gene; IRAK1 gene; Immune; Immune signaling; Interleukin 7 Receptor; Interleukin 8A Receptor; Interleukin Activation; Interleukin-8; Interleukin-8B Receptor; Marrow; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; NUP98 gene; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Prognostic Factor; Recurrent disease; Relapse; Role; Sampling; Signal Pathway; Testing; Transfusion; Xenograft procedure; cell growth; chemotherapy; clinical application; clinical efficacy; clinically relevant; cohort; conventional therapy; efficacy testing; humanized antibody; improved; in vivo; in vivo Model; inhibitor/antagonist; knock-down; leukemia; leukemic transformation; mouse model; new therapeutic target; novel; outcome forecast; overexpression; prevent; progenitor; relapse prediction; response; self-renewal; small hairpin RNA; small molecule; stem; stem cells; therapeutic target

MDS is a generally incurable hematologic disorder associated with disease initiating stem cells that are not eliminated by conventional therapies and need to be targeted for potentially curative strategies. We recently demonstrated that aberrant hematopoietic stem cells are expanded in MDS, can persist during phenotypic remissions and can predict relapse. In preliminary studies, we demonstrate that Interleukin 8 (IL8) is consistently and selectively overexpressed in stem cells from MDS patients. The receptor for IL8, CXCR2, is also significantly increased in large MDS patient cohorts and is associated with a worse prognosis. Functionally, IL8/CXCR2 pathway inhibition by either shRNA-mediated knockdown or pharmacologic approaches abrogated proliferation in cell lines and primary MDS samples. Importantly, inhibition of the IL8/CXCR2 pathway selectively inhibited immature stem cells from MDS samples without an effect on healthy HSCs, and also had demonstrated efficacy in xenografts. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of IL-8/CXCR2 pathway on growth of disease initiating stem cells in MDS and determine the efficacy of clinically relevant inhibitors of this pathway in large cohort of primary human samples. Additionally, responses to IL8/CXCR2 inhibition with small molecules and a novel humanized antibody will be correlated with clinical and mutational subtypes to identify targetable subsets that will be sensitive to IL8/CXCR2 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for CXCR2 in initiation of dysplasia/disease progression in vivo by genetic deletion of CXCR2 in two mouse models of MDS. Along with the NUP-HOXD13 model; a novel model of MDS dysplasia and transformation which we have recently developed, induced by heterozygous PU.1 enhancer deletion, will be used to study the effect of CXCR2 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the mechanisms of activation of the IL8-CXCR2 pathway and determine its downstream effectors in MDS. IL8 is a known component of innate immune signaling cascades, and we will determine whether upstream immune activators, IL1RAP, TLRs and IRAK1/4 are driving overactivation of the IL8/CXCR2 pathway in MDS. We will also evaluate the activation and functional significance of PI3Kinase and MAP kinase pathways as downstream effectors of the IL8/CXCR2 pathway in MDS. Taken together, these studies will study the role of the IL8/CXCR2 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.

MDS是与疾病引发干细胞相关的通常无法治愈的血液学疾病 常规疗法不会消除这些方法，需要针对潜在的治疗方法 策略。我们最近证明了异常造血干细胞的扩展 MD，可以在表型恢复期间持续存在，并且可以预测复发。在初步研究中， 我们证明了白介素8（IL8）在干细胞中始终如一地过表达 来自MDS患者。在大型MDS中，IL8，CXCR2的受体也显着增加 患者队列，预后较差。在功能上，IL8/CXCR2途径 通过shRNA介导的敲低或药理方法的抑制作用 细胞系和主要MDS样品中的增殖。重要的是，抑制IL8/CXCR2 途径选择性地抑制来自MDS样品的未成熟干细胞，而对健康有影响 HSC，并且在异种移植物中也表现出功效。全面检查角色 在MDS中，AIM 1在此途径中将定义IL-8/CXCR2途径在生长中的功能作用 引发MDS干细胞的疾病并确定临床相关抑制剂的功效 这一途径是大量原代人类样本。此外，对IL8/CXCR2的响应 用小分子抑制和一种新型的人源化抗体将与临床和 突变亚型鉴定对IL8/CXCR2敏感的可靶向子集。 患者衍生的MDS异种移植物也将用于确定体内功效。 AIM 2意志 通过 CXCR2的遗传缺失在两种MD的小鼠模型中。以及NUP-HOXD13模型；一个 我们最近开发的MDS发育不良和转化的新型模型 杂合PU.1增强子缺失将用于研究CXCR2缺失对 引发干细胞和疾病进展的疾病。 AIM 3将确定 IL8-CXCR2途径的激活并确定其MDS中的下游效应子。 IL8是一个 先天免疫信号级联的已知组成部分，我们将确定上游是否 免疫激活剂，IL1RAP，TLR和IRAK1/4正在推动IL8/CXCR2的过度激活 MDS中的途径。我们还将评估PI3Kinase的激活和功能意义 和MAP激酶途径是MDS中IL8/CXCR2途径的下游效应子。拍摄 总之，这些研究将研究IL8/CXCR2途径在MDS发病机理和 确定其作为针对未成熟疾病的治疗靶标的潜力，引发了MDS中的细胞。