Investigating the role of the JAK/STAT3 Pathway in Clonal Proliferation and Immune Dysfunction in Myelodysplastic Syndrome

研究 JAK/STAT3 通路在骨髓增生异常综合征克隆增殖和免疫功能障碍中的作用

基本信息

批准号：
10223409
负责人：
PAUL B FERRELL
金额：
$ 16.27万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

Project Summary Myelodysplastic syndrome (MDS) is a heterogeneous group of pre-leukemic bone marrow failure disorders with a yearly incidence of approximately 13,000 in the U.S. Approximately one third of MDS patients will go on to develop acute myeloid leukemia (AML) with a dismal survival of 5-10%. Standard of care therapy only extends life by a median of 9 months in those requiring treatment and there is no cure for the disease outside of stem cell transplant. As the population ages, this disease will only become more common, thus there is an urgent need for more effective treatments in MDS. MDS pathogenesis is marked by both clonal myeloid proliferation and bone marrow immune dysfunction. In MDS bone marrow, a suppressive immune microenvironment develops in response to initial inflammation and contributes to the proliferation of developing blasts, which are free to grow unchecked by the immune system. In fact, myeloid-derived suppressor cells (MDSCs), myeloid cells which are suppressive to T cell function, have been implicated in disease pathogenesis and progression. The JAK/STAT3 pathway is critical in myeloid differentiation and is aberrantly activated in both myeloblasts and MDSCs, both of which increase as MDS progresses. In order to better understand JAK/STAT3 signaling in MDS, we will use single cell and functional genomic assays to profile STAT3 in primary patient samples, with particular focus on myeloblasts and MDSCs – two separate but central cells types in leukemic progression of MDS. Given our experience studying single cell phenotype and intracellular signaling in AML, we will adapt our methods to study MDS, with particular focus on p-STAT3. An advantage of this approach is the ability to measure all cells within a sample simultaneously and create single cell signaling profiles for each sample and in response to inhibition. We propose three specific aims to investigate JAK/STAT3 signaling in MDS. In Aim I, the basal and cytokine-induced responses of STAT3 signaling will be measured in banked MDS samples to understand the role of STAT3 signaling in leukemic progression. Aim II will test functional and signaling responses to various inhibitors of the JAK/STAT3 pathway. Finally, Aim III will determine the impact of standard therapy on JAK/STAT3 signaling and STAT3 targets in resistant MDS. Chromatin immunoprecipitation (ChIP-seq) will be used here in order to profile the gene targets of STAT3 in MDS. These studies will significantly contribute to our basic understanding of MDS and the therapeutic potential of the JAK/STAT3 pathway moving forward in this disease. This proposal is ultimately designed to allow Dr. Ferrell to develop further skills in mass cytometry, phospho- flow, immunology techniques and ChIP and to provide him with the critical mentoring and training necessary to become an independent physician-scientist.

项目概要骨髓增生异常综合征 (MDS) 是一组异质性白血病前期骨髓衰竭疾病，伴有在美国，每年大约有 13,000 例 MDS 患者发生。大约三分之一的 MDS 患者会继续患上这种疾病罹患急性髓性白血病 (AML)，生存率仅为 5-10%，标准护理治疗仅延长时间。需要治疗的患者的平均寿命延长 9 个月，并且除了干细胞疗法之外无法治愈该疾病随着人口老龄化，这种疾病只会变得更加普遍，因此刻不容缓。 MDS 发病机制的特点是克隆性骨髓增殖。和骨髓免疫功能障碍在 MDS 骨髓中，存在抑制性免疫微环境。响应最初的炎症而发展，并有助于发育中的原始细胞的增殖，这些原始细胞是事实上，骨髓源性抑制细胞 (MDSC) 可以不受免疫系统的抑制而自由生长。它们抑制 T 细胞功能，与疾病的发病机制和进展有关。 JAK/STAT3 通路在骨髓分化中至关重要，并且在成髓细胞和成髓细胞中均被异常激活。 MDSC，两者均随着 MDS 的进展而增加。为了更好地了解 MDS 中的 JAK/STAT3 信号传导，我们将使用单细胞和功能基因组分析来分析主要患者样本中的 STAT3，特别是重点关注成髓细胞和 MDSC——MDS 白血病进展中两种独立但核心的细胞类型。根据我们研究 AML 中单细胞表型和细胞内信号传导的经验，我们将调整我们的方法研究 MDS，特别关注 p-STAT3，这种方法的优点是能够测量所有细胞。同时在一个样品中，并为每个样品创建单细胞信号传导谱并响应我们提出了三个具体目标来研究 MDS 中的 JAK/STAT3 信号传导。将在储存的 MDS 样本中测量细胞因子诱导的 STAT3 信号反应，以了解 STAT3 信号传导在白血病进展中的作用 Aim II 将测试对各种疾病的功能和信号传导反应。最后，Aim III 将确定标准疗法对 JAK/STAT3 的影响。耐药 MDS 中的信号传导和 STAT3 靶点将在此处使用。为了分析 MDS 中 STAT3 的基因靶标，这些研究将对我们的基础研究做出重大贡献。了解 MDS 以及 JAK/STAT3 通路在该疾病中的治疗潜力。该提案的最终目的是让 Ferrell 博士进一步发展质谱流式细胞仪、磷酸化细胞术等方面的技能。流、免疫学技术和 ChIP，并为他提供必要的关键指导和培训成为一名独立的医师科学家。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel differentiation response with combination IDH inhibitor and intensive induction therapy for AML.

IDH 抑制剂联合治疗和 AML 强化诱导治疗的新型分化反应。

DOI：
发表时间：
2021
期刊：
影响因子：
7.5
作者：
Mason, Emily F;Pozdnyakova, Olga;Roshal, Mikhail;Fathi, Amir T;Stein, Eytan M;Ferrell, P Brent;Shaver, Aaron C;Frattini, Mark;Wang, Hongfang;Hua, Lei;Mu, Jimmy;Choe, Sung;Xu, Rengyi;Almon, Caroline;Cooper, Michael;Stone, Richard M;Hasserji
通讯作者：
Hasserji

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes.

骨髓增生异常综合征的免疫调节紊乱及其治疗靶点。