Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

慢性粒单核细胞白血病 (CMML) 的分子和细胞机制

• 批准号: 8469968
• 负责人: Jing Zhang
• 金额: $ 0.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469968
• 关键词: Abnormal Granulocyte; Acute Myelocytic Leukemia; Address; Affect; Apoptosis; Bone Marrow Transplantation; Candidate Disease Gene; Cell Proliferation; Cell Survival; Cells; Chronic Myelomonocytic Leukemia; Cytokine Signaling; Diagnosis; Disease; Elderly; Etiology; Event; Frequencies; Gene Mutation; Genes; Genetic; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Hematologic Neoplasms; Hematopoietic stem cells; Human; Hypersensitivity; Lead; Lesion; MEKs; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Myeloproliferative disease; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Property; RUNX1 gene; Regulation; Research; Role; Sampling; Signal Pathway; Signal Transduction; Solid; Validation; Variant; cell growth; effective therapy; insight; mouse model; neoplastic cell; novel; senescence; therapeutic target; tumor initiation

DESCRIPTION (provided by applicant): Chronic myelomonocytic leukemia (CMML) is a devastating cancer for which there is currently no effective therapy. Approximately 20% of CMML cases evolve to acute myelogenous leukemia (AML) soon after their initial diagnosis. Oncogenic NRAS mutations, which are among the most frequently identified genetic mutations in myeloid diseases, are identified in 17-60% of CMML cases, including cases that transform to AML. However, it remains elusive how oncogenic, endogenously arising NRAS mutations leads to CMML and its transformation to AML. Recently, we established a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the endogenous Nras locus in which ~95% of recipient mice develop a myeloproliferative (MP) disease remarkably resembling the MP variant of human CMML. Our preliminary results suggest that endogenous oncogenic Nras signaling promotes HSC proliferation and mobility rather than apoptosis and senescence. We propose that genetically altered HSCs initiate and maintain CMML in this model. In addition, similar to what occurs in patients with CMML, aberrant GM-CSF (granulocyte-macrophage colony stimulating factor) signaling is a signature of our model, primarily regulating expansion of granulocytic/monocytic precursors. We hypothesize that this aberrant signaling drives inappropriate cell growth and survival during disease initiation and progression, and thus could constitute a valuable therapeutic target. Because CMML occurs after a prolonged latency accompanied by multiple additional genetic lesions in our model, we further hypothesize that, as for human CMML, oncogenic NRAS cooperates with mutations in other genes to either induce CMML or lead to CMML transformation to AML. As a part of our long-term goal to understand the molecular and cellular mechanisms in tumor initiation, progression, and malignant transformation, in this application we propose: 1) To determine the effects of endogenous oncogenic Nras signaling on the properties of HSCs and examine whether HSCs expressing oncogenic Nras initiate and maintain CMML; 2) To determine whether aberrant GM-CSF signaling is essential to establish and/or maintain oncogenic Nras-initiated CMML-like phenotypes; 3) To identify novel pathogenic origins involved in CMML and/or its transformation to AML using CMML patient samples and to validate cooperating mutations of oncogenic NRAS in our murine model of CMML. Successful accomplishment of the proposed studies will not only provide insights into the pathogenesis, progression, and transformation of CMML, but may also lead to novel insights into HSC regulation, aberrant cytokine signaling, and cooperating mutations in oncogenic NRAS- associated myeloid diseases in general.

描述（由申请人提供）：慢性脊髓细胞性白血病（CMML）是一种毁灭性的癌症，目前尚无有效的治疗。最初诊断后不久，大约20％的CMML病例演变为急性骨髓性白血病（AML）。在17-60％的CMML病例中鉴定出最常见的髓样疾病遗传突变之一的致癌NRA突变，包括转化为AML的病例。然而，仍然难以捉摸的致癌性，内源性内源性的NRA突变导致CMML及其转化为AML。最近，我们建立了一个具有肿瘤性G12D突变的小鼠骨髓移植模型，该模型在内源性NRAS基因座中有一个骨髓的骨髓小鼠（MP）疾病，与人类CMML的MP变体相似。我们的初步结果表明，内源性致癌NRAS信号传导促进了HSC的增殖和迁移率，而不是凋亡和衰老。我们提出，在该模型中，基因改变的HSC启动并维持CMML。此外，类似于CMML患者，异常GM-CSF（粒细胞 - 巨噬细胞菌落刺激因子）信号传导是我们模型的签名，主要是调节粒细胞/单核细胞前体的扩张。我们假设这种异常信号导致疾病开始和进展过程中不适当的细胞生长和存活，因此可能构成有价值的治疗靶点。由于CMML在延长潜伏期后发生并在我们的模型中伴有多个其他遗传病变，因此我们进一步假设，对于人CMML，致癌NRAS与其他基因中的突变合作，以诱导CMML或导致CMML转化为AML。作为我们长期目标的一部分，是了解肿瘤起始，进展和恶性转化中的分子和细胞机制，在本应用中，我们建议：1）确定内源性致癌NRAS信号传导对HSC的性质的影响并检查表达Oncenic NRAS启动和维持CMML的HSC的HSC； 2）确定异常的GM-CSF信号传导是否对于建立和/或维持致癌的NRAS引起的CMML样表型至关重要； 3）在我们的CMML鼠模型中，使用CMML患者样品鉴定参与CMML和/或其转化为AML的新型致病起源，并验证致癌NRA的合作突变。成功完成拟议的研究不仅将提供有关CMML的发病机理，进展和转化的见解，而且还可能导致对HSC调节，异常细胞因子信号传导的新见解以及一般而言。