Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)

描述（由申请人提供）：慢性髓细胞白血病（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病例在最初诊断后很快发展为急性髓性白血病（AML）。致癌性NRAS突变是髓系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，致癌的内源性NRAS突变如何导致CMML及其向AML的转化仍然是一个谜。最近，我们建立了一种小鼠骨髓移植模型，该模型在内源性Nras位点上含有致癌基因G12D突变，其中约95%的受体小鼠发生骨髓增生性（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信号促进HSC增殖和迁移，而不是凋亡和衰老。我们认为基因改变的造血干细胞在该模型中启动并维持cml。此外，与CMML患者类似，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一个特征，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。由于在我们的模型中，CMML是在长时间潜伏期后发生的，并伴有多个额外的遗传病变，因此我们进一步假设，对于人类CMML，致癌的NRAS与其他基因的突变合作，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，在本应用程序中，我们提出：1)确定内源性致癌Nras信号对造血干细胞特性的影响，并检查表达致癌Nras的造血干细胞是否启动和维持CMML；2)确定异常的GM-CSF信号是否对建立和/或维持致癌的nras启动的cmml样表型至关重要；3)利用CMML患者样本确定涉及CMML和/或其向AML转化的新的致病来源，并在我们的小鼠CMML模型中验证致癌NRAS的合作突变。这些研究的成功完成不仅将为CMML的发病机制、进展和转化提供新的见解，而且还可能导致对一般致癌性NRAS相关髓系疾病的HSC调节、异常细胞因子信号传导和协同突变的新见解。

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.