Foxo transcription factors are required for maintenance of acute myeloid leukemia

Foxo 转录因子是维持急性髓系白血病所必需的

• 批准号: 8551381
• 负责人: Stephen Matthew Sykes
• 金额: $ 16.26万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551381
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Affect; Cancer Biology; Cell Death; Cell physiology; Cells; Data Set; Development; Diagnosis; Diagnostic; Disease Progression; Drug usage; Enzymes; Event; Family; Frequencies; Gene Expression; Gene Family; Genes; Genetic; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; In Vitro; Incidence; Individual; Investigation; JNK-activating protein kinase; Leukocytes; MAPK8 gene; Maintenance; Malignant Neoplasms; Mission; Modeling; Molecular; Molecular Abnormality; Molecular Profiling; Mus; National Cancer Institute; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Population; Pre-Clinical Model; Recurrent disease; Regulation; Relapse; Resistance; Role; SP600125; Sampling; Signal Pathway; Signal Transduction; Stress; Survival Rate; Toxic effect; abstracting; base; cancer cell; cancer therapy; cell growth; chemotherapy; design; improved; in vivo; inhibitor/antagonist; jun Oncogene; killings; leukemia; leukemogenesis; mortality; mouse model; novel; outcome forecast; research study; tool; transcription factor; treatment strategy

7. PROJECT SUMMARY/ABSTRACT: AML is a blood cancer that arises from the uncontrolled expansion of immature white blood cells. AML patients display an extraordinarily high rate of mortality, with only 23% surviving beyond 5 years. This poor prognosis results from both a high incidence of leukemia relapse and the ineffectiveness and toxicity of current therapies. While these alarming realities demand the development of more effective AML chemotherapies, this notion is complicated by two major factors. First, a small but distinct fraction of leukemia cells (called leukemia-initiating cells or LICs) are able to evade conventional drugs and cause leukemia relapse. Second, AML has many different sub-types, each with different genetic abnormalities that limit the ability to design broad-spectrum anti- AML drugs. Therefore, identifying and targeting common molecular irregularities specifically found in LICs is a critical basis for developing successful broad-based AML therapies. Using a gene expression dataset derived from a large human AML sample set, we have identified that the FOXO family of genes are inappropriately activated in ~40% of AML cases. Using a mouse model of AML we also found that FOXOs are critical regulators of LICs. Further investigation revealed that approximately 60% of the leukemic samples were resistant to FOXO suppression. Those cells that were FOXO insensitive had abnormalities of another pathway, the JNK gene family. Inhibition of both FOXO and JNK, using drugs to inhibit JNK enzymes, resulted in marked killing of even the resistant cancer cells. We now aim to determine the downstream effectors of the FOXO and JNK pathways that allow these genes to promote leukemogenesis. Specifically, we will examine how the activities of the oncogenes c-JUN and ¿- catenin are affected by manipulation of the FOXO and JNK pathways. Further, we want to evaluate whether pharmacological exploitation of these pathways provides a proof-in-principal strategy for the treatment of AML. We will accomplish this by evaluating how the combined inhibition of FOXO and JNK signaling impacts human AML cell growth and LIC function. We believe that these proposed experiments align perfectly with the National Cancer Institute's mission to uncover new molecular signatures in human cancer that could improve diagnostic tools and provide platforms for the design of new, more effective anti-cancer therapies. Additionally, addressing these questions will: 1. Further define the unrecognized role of FOXO and JNK signaling pathways in cancer biology. 2. Provide novel proof-of-concept strategies for the treatment and diagnosis of AML. 3. Improve our understanding of the molecular networks that support human leukemogenesis in vivo.

7。项目摘要/摘要： AML是一种血液癌，是由未成熟白细胞的不受控制的膨胀引起的。 AML患者 表现出极高的死亡率，只有23％的人存活超过5年。这种不良的预后 来自白血病继电器的高性入射以及当前疗法的无效和毒性的结果。 尽管这些令人震惊的现实需要开发更有效的AML化学疗法，但该观念是 由两个主要因素复杂。首先，一小部分但独特的白血病细胞（称为白血病发射 细胞或lics）能够逃避常规药物并引起白血病缓解。第二，AML有很多 不同的亚类型，每个类型都有不同的遗传异常 AML药物。因此，识别和靶向特定发现的常见分子不规则性 LIC是开发成功基于广泛的AML疗法的关键基础。 使用来自大型人类AML样品集的基因表达数据集，我们已经确定 在约40％的AML病例中，FOXO基因家族被不适当地激活。使用AML的鼠标模型我们 还发现Foxos是LIC的关键调节者。进一步的调查显示，约有60％ 白血病样品对FOXO抑制具有抗性。那些不敏感的细胞 JNK基因家族的另一种途径的异常。抑制FOXO和JNK，使用药物抑制 JNK酶，即使是抗性癌细胞也显着杀死。 现在，我们旨在确定FOXO和JNK途径的下游效应，这些途径允许这些基因 促进白血病。具体而言，我们将研究Oncogenes C -Jun和„的活动如何 Catenin受Foxo和JNK Pathways操纵的影响。此外，我们想评估是否 对这些途径的药理剥削为治疗AML的治疗提供了校对策略。 我们将通过评估FOXO和JNK信号的联合抑制如何影响人类来实现这一目标 AML细胞生长和LIC功能。我们认为这些提出的实验与 国家癌症研究所（National Cancer Institute 诊断工具，并为设计新的，更有效的抗癌疗法提供平台。此外， 解决这些问题将： 1。进一步定义了FOXO和JNK信号通路在癌症生物学中的无法识别的作用。 2。为AML的治疗和诊断提供新颖的概念证明策略。 3。提高我们对支持人类白血病发生的分子网络的理解。