STAT3 inhibition as a therapeutic strategy against MDS stem cells

STAT3 抑制作为针对 MDS 干细胞的治疗策略

基本信息

批准号：
10206262
负责人：
Ulrich Steidl
金额：
$ 53.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206262
关键词：
Acute Myelocytic Leukemia Apoptotic Azacitidine Biological Biological Assay Cell Line Cells ChIP-seq Clinical Data Development Disease Disease Progression Disease remission Dysmyelopoietic Syndromes Dysplasia Enhancers Evaluable Disease Future Genetic Genomics Growth Hematological Disease Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro MCL1 gene Marrow Medicine Modeling Molecular Morphology Mutation NUP98 gene Nature Outcome Pathogenesis Pathway interactions Patients Phenotype Population Prognosis Recurrent disease Relapse Role STAT3 gene Sampling Solid Neoplasm Source Testing Therapeutic Xenograft procedure cancer stem cell chemotherapy clinical application clinical efficacy clinically relevant cohort conventional therapy curative treatments efficacy testing epigenomics granulocyte-monocyte progenitors improved in vivo in vivo Model inhibitor/antagonist leukemia leukemic transformation mouse model novel overexpression prevent progenitor relapse prediction response self-renewal stem stem cell growth stem cells therapeutic target transcription factor transcriptomics

Acute Myelocytic Leukemia Apoptotic Azacitidine Biological Biological Assay Cell Line Cells ChIP-seq Clinical Data Development Disease Disease Progression Disease remission Dysmyelopoietic Syndromes Dysplasia Enhancers Evaluable Disease Future Genetic Genomics Growth Hematological Disease Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro MCL1 gene Marrow Medicine Modeling Molecular Morphology Mutation NUP98 gene Nature Outcome Pathogenesis Pathway interactions Patients Phenotype Population Prognosis Recurrent disease Relapse Role STAT3 gene Sampling Solid Neoplasm Source Testing Therapeutic Xenograft procedure cancer stem cell chemotherapy clinical application clinical efficacy clinically relevant cohort conventional therapy curative treatments efficacy testing epigenomics granulocyte-monocyte progenitors improved in vivo in vivo Model inhibitor/antagonist leukemia leukemic transformation mouse model novel overexpression prevent progenitor relapse prediction response self-renewal stem stem cell growth stem cells therapeutic target transcription factor transcriptomics

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项目摘要

Myelodysplastic syndromes (MDS) are generally incurable hematologic disorders 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. STAT3 is a transcription factor that was found to be overexpressed in MDS stem cells and higher expression was associated with an adverse prognosis in a large cohort of patients. We also obtained proof-of-concept data that inhibition of STAT3 can target malignant stem cells while sparing healthy control stem and progenitors, thus identifying it as a potential therapeutic target in MDS. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of STAT3 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, in vitro and in vivo efficacy of a clinically applicable, anti-sense inhibitor (AZD-9150) against a large number of primary MDS samples will be correlated with clinical and mutational subtypes to identify subsets that will be sensitive to STAT3 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for STAT3 in initiation of dysplasia/disease progression in vivo by genetic deletion of STAT3 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 STAT3 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the downstream effectors of STAT3 activation in MDS. Combination of Chip-seq and transcriptomic profiling will be used to identify direct targets of STAT3 activation, that will tested in functional assays in MDS models. We will also determine the role of MCL-1 as a downstream anti-apoptotic target of STAT3 activation in MDS stem cells. Identification of critical downstream effectors will improve our molecular understanding of the STAT3 pathway in MDS and will be instrumental to develop more specific and potent strategies to inhibit this pathway. Taken together, these studies will study the role of the STAT3 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.

骨髓增生综合征（MDS）通常是无法治愈的血液学疾病疾病引发的干细胞未被常规疗法消除，需要针对潜在的治愈策略。我们最近证明了异常造血干细胞在MDS中扩展，在表型解散期间可以持续存在，并且可以预测复发。 STAT3是一个转录因子，发现在MDS中过表达干细胞和较高的表达与大量队列中的不良预后有关患者。我们还获得了概念验证数据，即抑制STAT3可以针对恶性肿瘤干细胞在保留健康的对照茎和祖细胞的同时，将其识别为潜力 MDS中的治疗靶标。要全面检查该途径在MDS中的作用，AIM 1 将定义STAT3在MDS和确定该途径在大量初级队列中的临床相关抑制剂的疗效人类样品。另外，在体外和体内功效针对大量主要MDS样品的抑制剂（AZD-9150）将与临床和突变亚型，以鉴定对STAT3抑制敏感的亚群。患者衍生的MDS异种移植物也将用于确定体内功效。 AIM 2意志确定STAT3在体内启动发育异常/疾病进展过程中的需求 MDS的两个小鼠模型中STAT3的遗传缺失。以及NUP-HOXD13模型；一个我们最近开发的，诱导的新型MDS发育不良和转化模型通过杂合PU.1增强子缺失，将用于研究STAT3缺失对引发干细胞和疾病进展的疾病。 AIM 3将识别下游 MDS中Stat3激活的效应子。芯片序列和转录组分析的组合将用于识别STAT3激活的直接目标，该目标将在功能测定中测试 MDS型号。我们还将确定MCL-1作为下游抗凋亡靶标的作用 MDS干细胞中的STAT3激活。识别关键下游效应子将改善我们对MDS中STAT3途径的分子理解，将有助于发展更具体而有力的策略来抑制这一途径。两者一起，这些研究将研究STAT3途径在MDS发病机理中的作用，并确定其作为A的潜力针对未成熟的治疗靶标，疾病引发了MDS中的细胞。