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.项目总结/摘要： 急性髓细胞白血病是一种血液癌症，由不成熟的白色血细胞不受控制的扩增引起。AML患者 死亡率非常高，只有23%的人存活超过5年。这种预后不良 这是由于白血病复发的高发生率和目前治疗的无效性和毒性。 虽然这些令人担忧的现实要求开发更有效的AML化疗，但这一概念是可行的。 有两个主要的因素。首先，一小部分但不同的白血病细胞（称为白血病起始细胞）， 细胞或LIC）能够逃避常规药物并导致白血病复发。其次，AML有许多 不同的亚型，每一种都有不同的遗传异常，限制了设计广谱抗肿瘤药物的能力。 AML药物因此，识别和靶向常见的分子不规则性，特别是在 LIC是开发成功的广泛AML疗法的关键基础。 使用来自大型人类AML样本集的基因表达数据集，我们已经确定， FOXO基因家族在约40%的AML病例中被不适当地激活。使用AML小鼠模型， 还发现FOXO是LIC的关键监管者。进一步调查显示，大约60%的 白血病样本对FOXO抑制有抵抗力。那些对FOXO不敏感的细胞 另一个途径，JNK基因家族的异常。抑制FOXO和JNK，使用药物抑制 JNK酶，导致甚至耐药癌细胞的显著杀伤。 我们现在的目标是确定FOXO和JNK通路的下游效应子，这些效应子使这些基因能够 促进白血病发生。具体来说，我们将研究癌基因c-JUN和c-JUN的活性如何影响癌基因的表达。 连环蛋白受到FOXO和JNK途径的操纵的影响。此外，我们还想评估 这些途径的药理学开发提供了治疗AML的原理验证策略。 我们将通过评估FOXO和JNK信号传导的联合抑制如何影响人类免疫系统来实现这一点。 AML细胞生长和LIC功能。我们认为，这些拟议的实验完全符合 国家癌症研究所的使命是发现人类癌症中的新分子特征， 诊断工具，并为设计新的，更有效的抗癌疗法提供平台。此外，本发明还 解决这些问题将： 1.进一步明确FOXO和JNK信号通路在癌症生物学中未被认识的作用。 2.为AML的治疗和诊断提供新的概念验证策略。 3.提高我们对支持体内人类白血病发生的分子网络的理解。