Targeting PLCG1 in AML1-ETO-positive acute myeloid leukemia (AML)
靶向 PLCG1 治疗 AML1-ETO 阳性急性髓系白血病 (AML)
基本信息
- 批准号:389538676
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2017
- 资助国家:德国
- 起止时间:2016-12-31 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by the accumulation of immature and proliferating blasts in the bone marrow, peripheral blood and other organs. Molecular heterogeneity of AML remains a major therapeutic challenge. Different genomic AML profiles contribute to disease biology and translate to variable outcomes. This molecular and clinical heterogeneity may also depend on the cellular origin of the different AML subtypes. On the other hand, presence of specific aberrations can create secondary dependencies and vulnerabilities. Within the first funding period we aimed to identify novel molecular targets for fusion oncogene–induced acute myeloid leukemia (AML). We performed high-resolution proteomic analysis. In AML1-ETO (AE)-driven AML, we uncovered a deregulation of phospholipase C (PLC) signaling. Of note, highest expression levels were found in AML harboring the balanced translocation t(8;21), which gives rise to the oncogenic fusion AML1-ETO. We identified PLCgamma1 (PLCG1) as a specific target of the AE fusion protein that is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in a newly developed conditional mouse model and in human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of calcium-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO1 leukemic stem cells. While the upstream regulation of PLCG1 in AE-AML has been characterized, its downstream regulation and mechanistic function remains elusive. According to our proposed working program we will identify relevant effectors and specify dependencies of PLCG1 in AE-AML and aim to uncover mechanistic roles of PLCG1 to facilitate targeting of PLCG1 in AE-AML. Using CRISPR-mediated screens, we have identified relevant domains of PLCG1 indicating targetable regions. Using global phospho-proteome analysis and functional genome editing approaches we will define effectors and dependencies of PLCG1 in AML1-ETO (AE) driven AML. Using the conditional mouse model created in the first funding period, we will conduct rescue experiments, genetic perturbation of relevant PLCG1 domains and interactome analyses to uncover targetable molecular mechanisms downstream of PLCG1 in AML1-ETO AML.
急性髓系白血病(acute myeloid leukemia,AML)是一种克隆性造血系统疾病,其特征是骨髓、外周血和其他器官中未成熟和增殖的原始细胞聚集。AML的分子异质性仍然是一个主要的治疗挑战。不同的基因组AML谱有助于疾病生物学,并转化为可变的结果。这种分子和临床异质性也可能取决于不同AML亚型的细胞来源。另一方面,特定偏差的存在可能会产生次级依赖性和脆弱性。在第一个资助期内,我们的目标是确定融合癌基因诱导的急性髓性白血病(AML)的新分子靶点。我们进行了高分辨率蛋白质组学分析。在AML 1-ETO(AE)驱动的AML中,我们发现了磷脂酶C(PLC)信号转导的失调。值得注意的是,在携带平衡易位t(8;21)的AML中发现了最高表达水平,其产生致癌融合AML 1-ETO。我们确定PLC γ 1(PLCG 1)作为AE融合蛋白的特异性靶点,该融合蛋白在AE与基因间调控DNA元件结合后诱导。在新开发的条件性小鼠模型和人AML中,PLCG 1的遗传失活抑制了体内AML 1-ETO依赖性自我更新程序、白血病增殖和白血病维持。相比之下,PLCG 1对正常造血干细胞和祖细胞功能无影响。这些发现被扩展到AML 1-ETO AML细胞中钙信号的药理学扰动并得到证实,表明PLCG 1途径构成了AML 1-ETO 1白血病干细胞的重要治疗靶点。虽然PLCG 1在AE-AML中的上游调控已被表征,但其下游调控和机制功能仍然难以捉摸。根据我们提出的工作计划,我们将识别相关效应物并指定PLCG 1在AE-AML中的依赖性,并旨在揭示PLCG 1的机制作用,以促进AE-AML中PLCG 1的靶向作用。使用CRISPR介导的筛选,我们已经确定了PLCG 1的相关结构域,指示可靶向区域。使用全局磷酸化蛋白质组分析和功能基因组编辑方法,我们将定义PLCG 1在AML 1-ETO(AE)驱动的AML中的效应子和依赖性。使用在第一个资助期创建的条件性小鼠模型,我们将进行拯救实验,相关PLCG 1结构域的遗传扰动和相互作用组分析,以揭示AML 1-ETO AML中PLCG 1下游的靶向分子机制。
项目成果
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