Inflammation as determinant of clonal selection in MPN progression

炎症是 MPN 进展中克隆选择的决定因素

基本信息

批准号：
9788508
负责人：
Nadia Carlesso
金额：
$ 53.69万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788508
关键词：
Acute Myelocytic Leukemia Address Affect Aging Animal Model Automobile Driving Bone Marrow Carcinoma Cause of Death Cells Chronic Clinical Clonal Evolution Clonal Expansion Complement DNA DNA delivery Data Analyses Disease Disease Progression Disease remission Endothelium Event Evolution Exhibits Genetic Genetic study Hematopoiesis Hematopoietic Hematopoietic Neoplasms Human Inflammation Inflammatory Information Resources Management Investigation JAK2 gene Knockout Mice Lead Leukemic Cell Link Malignant - descriptor Malignant Neoplasms Mediator of activation protein MicroRNAs Modeling Molecular Mus Mutation Myelofibrosis Myelogenous Myeloid Cells Myeloproliferative disease NF-kappa B Neoadjuvant Therapy Neoplasms Patients Play Predisposition Process Proteins Relapse Risk Role Secondary Myelofibrosis Signal Transduction Solid Specimen System Testing Therapeutic Therapeutic Intervention Transplantation Tumor Promotion Up-Regulation Work actionable mutation base bcr-abl Fusion Proteins chemokine cytokine exome sequencing improved in vivo in vivo Model inflammatory milieu inhibitor/antagonist intravital microscopy leukemia treatment leukemic transformation mouse model notch protein novel novel therapeutic intervention outcome forecast patient stratification prevent progenitor prognostic tool tumor progression

项目摘要

Background. Our current understanding of the mechanisms for Bcr/Abl-negative myeloprolifereative neoplasia (MPN) involves recognition of restricted MPN driver mutations targeting JAK2, MPL, or CALR, and of an inflammatory microenvironment, characterized by heightened expression and secretion of cytokines and chemokines. However, the contribution of inflammation to MPN progression has not been addressed. Similarly, the causes that lead to an inflammatory microenvironment in MPN have not been defined. Interestingly, the recent observation that clonal hematopoiesis of indeterminate potential (CHIP) exhibit accumulating mutations that correlate with aging, strongly suggests a role for inflammation in clonal selection and disease progression. Preliminary Results. We have generated an animal model of chronic inflammation in which loss of Notch signaling in the BM endothelium (Tie2CreERRBPJKO mice) induces upregulation of the microRNA miR-155, increased NF-kB signaling and pro-inflammatory cytokines resulting in a MPN-like disease within 8-12 months. Importantly, this microenvironmental inflammatory milieu greatly accelerates expansion of hematopoietic cells containing JAK2V617F or TET2-/- mutations. Hypothesis. We propose a model in which: a) prolonged exposure of JAK2V616F or TET2-/- hematopoietic cells to a chronic inflammatory BM niche will favor clonal expansion, acquisition of additional mutations and selection of aggressive clones leading to MPN progression into myelofibrosis or/and AML; b) upregulation of miR-155 plays a pivotal role in generating a vicious cycle of “malignant” inflammation driving MPN progression. Aims. To test these hypotheses we propose: (1) To determine whether exposure of hematopoietic cells to an inflammatory BM niche leads to clonal selection and disease progression in in vivo models of JAK2V617F and TET2-/- driven MPN; (2) To define the functional relationship between miR-155 and NF-kB in promoting MPN progression, and; (3) To identify an inflammatory signature in the human BM microenvironment correlating with MPN progression. Strategy. To this end, we will use Tie2CreERRBPJKO mice as a genetically-controlled animal model of chronic inflammation, in combination with JAK2V616F or TET2-/- models in transplant settings. In addition, kB-Ras-/- and miR155-/- mice will be used to address the role of miR-155 and NF-kB in disease progression. A lentiviral-DNA barcoding system combined with fluorescent proteins will be used to follow clonal evolution in vivo. This approach will be complemented by whole exome sequencing to identify mutations, and by intravital microscopy, to visualize clones interactions with defined BM niches. Finally, the efficacy of a novel anti-miR-155 therapeutic approach will be tested, and MPN BM specimens will be analyzed to identify inflammatory signatures correlating with disease progression. Relevance. We believe that accomplishment of this work will have impact on the understanding and management of MPN, providing a solid rationale for early therapeutic intervention to suppress chronic inflammation and thus, preventing MPN progression.

背景。我们目前对BCR/ABL阴性脊髓脂性肿瘤机制的理解（MPN）涉及识别针对JAK2，MPL或CALR的受限MPN驱动突变，以及炎症性微环境，其特征是细胞因子的表达和分泌升高和分泌趋化因子。但是，尚未解决炎症对MPN进展的贡献。相似地，尚未定义导致MPN炎症微环境的原因。有趣的是，最近观察到不确定电势（CHIP）暴露的累积突变的克隆造血这与衰老相关，强烈暗示炎症在克隆选择和疾病进展中的作用。初步结果。我们已经产生了一种慢性炎症的动物模型，其中缺口丧失 BM内皮（TIE2CREERRBPJKO小鼠）中的信号传导诱导MicroRNA miR-155的上调， NF-KB信号传导和促炎性细胞因子增加，导致8-12个月内产生类似MPN的疾病。重要的是，这种微环境炎症环境极大地加速了造血细胞的膨胀包含JAK2V617F或TET2 - / - 突变。假设。我们提出了一个模型，其中：a）长时间暴露 jak2v616f或tet2 - / - 造血细胞属于慢性炎症性BM壁ni将有利于克隆膨胀，获取其他突变和选择攻击性克隆，导致MPN进展为骨髓纤维化或/和AML； b）miR-155的上调在产生恶性循环中起关键作用 “恶性”炎症驱动MPN进展。目标。为了检验这些假设，我们提出：（1）确定造血细胞暴露于炎症BM生态位是否导致克隆选择和 JAK2V617F和TET2 - / - 驱动MPN的体内模型中的疾病进展；（2）定义功能 miR-155和NF-KB之间的关系在促进MPN进展方面，并且；（3）识别炎症人类BM微环境中的签名与MPN进展相关。战略。为此，我们将使用TIE2CREERRBPJKO小鼠作为慢性感染的一般控制动物模型在移植设置中使用JAK2V616F或TET2 - / - 模型。此外，KB-RAS - / - 和miR155 - / - 小鼠将用于解决miR-155和NF-KB在疾病进展中的作用。慢病毒-DNA条形码系统合并荧光蛋白将用于体内克隆进化。这种方法将由整个外显子组测序以识别突变和插入显微镜，以可视化克隆的相互作用具有定义的BM壁ni。最后，将测试一种新型抗MIR-155治疗方法的效率，并将分析MPN BM标本，以鉴定与疾病进展相关的炎症特征。关联。我们认为，这项工作的完成将影响理解和 MPN的管理，为早期热干预提供了坚实的理由，以抑制慢性炎症，从而防止MPN进展。