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

基本信息

批准号：
8520252
负责人：
Jing Zhang
金额：
$ 30.06万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/8520252
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

项目摘要

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）：慢性粒单核细胞白血病（CMML）是一种毁灭性的癌症，目前尚无有效的治疗方法。大约 20% 的 CMML 病例在初次诊断后不久就会发展为急性髓性白血病 (AML)。致癌性 NRAS 突变是骨髓疾病中最常见的基因突变之一，在 17-60% 的 CMML 病例中被发现，包括转化为 AML 的病例。然而，致癌性、内源性 NRAS 突变如何导致 CMML 及其向 AML 的转化仍不清楚。最近，我们建立了在内源性 Nras 基因座中含有致癌性 G12D 突变的小鼠骨髓移植模型，其中约 95% 的受体小鼠出现骨髓增生（MP）疾病，与人类 CMML 的 MP 变体非常相似。我们的初步结果表明，内源性致癌 Nras 信号传导促进 HSC 增殖和迁移，而不是凋亡和衰老。我们建议基因改变的 HSC 在该模型中启动并维持 CMML。此外，与 CMML 患者中发生的情况类似，异常的 GM-CSF（粒细胞-巨噬细胞集落刺激因子）信号传导是我们模型的特征，主要调节粒细胞/单核细胞前体的扩张。我们假设这种异常信号传导在疾病发生和进展过程中驱动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 在我们的模型中发生在长时间的潜伏期并伴有多个额外的遗传损伤后，我们进一步假设，对于人类 CMML，致癌 NRAS 与其他基因的突变配合，诱导 CMML 或导致 CMML 转化为 AML。作为我们了解肿瘤发生、进展和恶性转化的分子和细胞机制的长期目标的一部分，在本申请中，我们建议：1) 确定内源性致癌 Nras 信号传导对 HSC 特性的影响，并检查表达致癌 Nras 的 HSC 是否启动并维持 CMML； 2) 确定异常的 GM-CSF 信号传导是否对于建立和/或维持致癌 Nras 引发的 CMML 样表型至关重要； 3) 使用 CMML 患者样本鉴定涉及 CMML 和/或其转化为 AML 的新致病起源，并在我们的 CMML 小鼠模型中验证致癌 NRAS 的协同突变。拟议研究的成功完成不仅将为 CMML 的发病机制、进展和转化提供见解，而且还可能为 HSC 调节、异常细胞因子信号传导以及致癌性 NRAS 相关骨髓疾病的协同突变提供新的见解。