Cell Competition in Myeloproliferative Neoplasms

骨髓增生性肿瘤中的细胞竞争

• 批准号: 10659053
• 负责人: Huichun Zhan
• 金额: $ 35.67万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659053
• 关键词: AMD3100; Acute leukemia; Aging; Allogenic; Biological Assay; Blood specimen; CD34+CD38- cell; CXCR4 Receptors; Cancer Relapse; Cell Compartmentation; Cell Count; Cell Line; Cell Maintenance; Cell physiology; Cells; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; DNA Sequence Alteration; Development; Disease; Dose; Evolution; Exposure to; Gene Expression Profile; Genetic; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homing; Human; Immune; Immunity; Immunosuppression; In Vitro; Individual; JAK2 gene; Ligands; Longterm Follow-up; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Mus; Mutation; Myeloproliferative disease; Normal Cell; Patients; Peptides; Phosphotransferases; Play; Population; Proliferating; Relapse; Reporting; Research Proposals; Risk; Role; Signal Transduction; Stem cell transplant; Stromal Cell-Derived Factor 1; System; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Transplantation; Tumor Stem Cells; Work; advanced disease; cell type; chemokine; curative treatments; exhaustion; experience; experimental study; hematopoietic stem cell expansion; human disease; human tissue; immunoregulation; in vivo; in vivo Model; induced pluripotent stem cell; knock-down; lentiviral-mediated; leukemia; mouse model; mutant; neoplastic cell; notch protein; overexpression; peripheral blood; prevent; progenitor; self-renewal; stem; stem cell differentiation; stem cell function; stem cells; stemness; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT The myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by hematopoietic stem cell expansion and increased risk of transformation to frank leukemia. The hematopoietic stem cell compartment in MPN is heterogeneous with the presence of both wild-type and JAK2V617F mutant cells in most patients with MPNs. Despite mutant cells bearing an in vitro proliferative advantage because of constitutive kinase activity, in some patients, there is little or no change in the mutant/wild-type cell ratio over long term follow up; while in others, MPN can evolve to acute leukemia and patients experience high relapse rates following allogeneic stem cell transplantation, the only curative treatment for these patients. JAK2V617F is also one of the common mutations associated with clonal hematopoiesis of indeterminate potential and most individuals with such clonal hematopoiesis do not convert to advanced disease. Utilizing in vitro co-culture assays and in vivo competitive transplantation assays, we demonstrated that the presence of wild-type cells can prevent the expansion of co- existing JAK2V617F mutant cells in a normal microenvironment. Delta-like ligand 1 (Dlk1), a noncanonical Notch ligand important in stem cell maintenance, was significantly inhibited in JAK2V617F mutant hematopoietic stem/progenitor cells with competition compared to mutant cells without competition. We also found that a mutant microenvironment can promote mutant cell expansion over wild-type cells. CXCL12, a chemokine critical for both hematopoietic stem cell maintenance and immune suppression, was up-regulated in the mutant microenvironment. Critically, both upregulated Dlk1 expression and dysregulated CXCL12 signaling have been reported in patients with MPNs. Based on these observations, we hypothesize that, in the hematopoietic system, competition between normal and neoplastic stem cells provides an essential mechanism to protect against cancer development. The objective of the proposed work is to determine whether normal cells could potentially be used as a therapeutic approach to control mutant clone expansion and the evolution of MPN to leukemia, in combination with approaches targeting the MPN tumor microenvironment. In particular, we propose the following two specific aims: 1) To elucidate the mechanisms by which wild-type cells prevent the expansion of JAK2V617F mutant cells in a normal hematopoietic microenvironment. The roles of Dlk1 deregulation in cell competition- induced JAK2V617F mutant stem cell suppression will be determined. 2) To study how the tumor immune microenvironment alters the competition between wild-type and JAK2V617F mutant cells. The roles of tumor- specific T cells and CXCL12 signaling in tumor microenvironment-induced mutant clonal expansion will be defined. We expect these studies will expand our understanding of the molecular mechanisms controlling the competitive interactions between normal and neoplastic cells, and how these mechanisms break down during cancer progression and relapse.

项目总结/摘要 骨髓增生性肿瘤（MPN）是以造血干细胞异常为特征的克隆性干细胞疾病。 细胞扩增和转化为弗兰克白血病的风险增加。造血干细胞 在MPN中的突变是异质的，在大多数MPN患者中存在野生型和JAK 2 V617 F突变细胞。 MPN。尽管突变细胞由于组成性激酶活性而具有体外增殖优势， 在一些患者中，在长期随访中突变/野生型细胞比率变化很小或没有变化;而在 其他人，MPN可演变为急性白血病，患者在异基因干细胞移植后复发率高。 细胞移植是治疗这些患者的唯一方法。JAK 2 V617 F也是常见的之一 与不确定潜力的克隆造血相关的突变，大多数具有这种克隆造血的个体 造血不会转化为晚期疾病。利用体外共培养试验和体内竞争性 移植试验中，我们证明了野生型细胞的存在可以阻止共- 在正常微环境中存在JAK 2 V617 F突变细胞。Delta-like ligand 1（Dlk 1），一种非经典Notch 在干细胞维持中重要的配体，在JAK 2 V617 F突变体造血细胞中被显著抑制， 干细胞/祖细胞与无竞争的突变细胞相比。我们还发现一个变种人 微环境可以促进突变体细胞相对于野生型细胞的扩增。CXCL 12，一种对两种细胞都至关重要的趋化因子 造血干细胞维持和免疫抑制，在突变体中上调 微环境重要的是，上调的Dlk 1表达和失调的CXCL 12信号传导已经被证实是一种重要的机制。 在MPN患者中报告。基于这些观察，我们假设，在造血系统中， 正常干细胞和肿瘤干细胞之间的竞争提供了一种重要的机制， 癌症发展这项工作的目的是确定正常细胞是否可能 可用作控制突变克隆扩增和MPN向白血病演变的治疗方法， 与靶向MPN肿瘤微环境的方法组合。我们特别提出以下建议： 两个具体目的：1）阐明野生型细胞阻止JAK 2 V617 F扩增的机制 正常造血微环境中的突变细胞。Dlk 1失调在细胞竞争中的作用- 将确定诱导的JAK 2 V617 F突变体干细胞抑制。2)为了研究肿瘤免疫 微环境改变了野生型和JAK 2 V617 F突变细胞之间的竞争。肿瘤的作用- 特异性T细胞和CXCL 12信号在肿瘤微环境诱导的突变克隆扩增中的作用将被 定义了我们希望这些研究将扩大我们对控制细胞凋亡的分子机制的理解。 正常细胞和肿瘤细胞之间的竞争性相互作用，以及这些机制在肿瘤形成过程中如何分解。 癌症进展和复发。