Foxo transcription factors are required for maintenance of acute myeloid leukemia

描述(申请人提供)：AML是一种血癌，由未成熟的白细胞不受控制的扩张引起。AML患者的死亡率非常高，只有23%的患者存活超过5年。这种不良的预后既是由于白血病复发的高发生率，也是目前治疗方法的无效和毒性所致。虽然这些令人震惊的现实要求开发更有效的急性髓细胞白血病化疗方法，但这一概念因两个主要因素而变得复杂。首先，一小部分但不同的白血病细胞(称为白血病启动细胞或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，每种亚型都有不同的基因异常，限制了设计广谱抗AML药物的能力。因此，识别和定位在LICs中发现的常见分子异常是开发成功的广泛AML治疗的关键基础。 使用来自人类AML大样本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。利用AML小鼠模型，我们还发现FOXO是LICs的关键调节因子。进一步的调查显示，大约60%的白血病样本对FOXO抑制具有抵抗力。那些对FOXO不敏感的细胞有另一种途径的异常，即JNK基因家族。同时抑制FOXO和JNK，使用药物抑制JNK酶，甚至可以显著杀死耐药的癌细胞。 我们现在的目标是确定FOXO和JNK通路的下游效应器，使这些基因能够促进白血病的发生。具体地说，我们将研究FOXO和JNK通路的操纵如何影响癌基因c-jun和catenin的活性。此外，我们希望评估这些途径的药理学利用是否为AML的治疗提供了一种原则上的证明策略。我们将通过评估FOXO和JNK信号的联合抑制如何影响人类AML细胞生长和LIC功能来实现这一点。我们相信，这些拟议的实验与国家癌症研究所的使命完美地结合在一起，即在人类癌症中发现新的分子签名，这些签名可以改进诊断工具，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.进一步明确FOXO和JNK信号通路在肿瘤生物学中的未知作用。 2.为急性髓细胞白血病的治疗和诊断提供新的概念验证策略。 3.提高我们对体内支持人类白血病发生的分子网络的理解。 公共卫生相关性：急性髓系白血病(AML)是一种血癌，每4名确诊患者中就有3人死亡。AML的高死亡率是疾病频繁复发(由称为白血病启动细胞(LICs)的罕见细胞引起)、靶向(或特异性)治疗不足以及传统化疗的高毒性累积的结果。我们已经确定了两个基因家族，FOXO[FOXO]和JNKS[垃圾]，它们是设计新型抗白血病疗法的理想靶点，因为这些基因结合在一起在大多数AML的LIC群体中异常活跃。

DESCRIPTION (provided by applicant): 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 conventiona 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. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) is a blood cancer that kills 3 out of 4 diagnosed patients. The high mortality of AML is the cumulative result of frequent disease relapse (caused by rare cells called leukemia-initiating cells (LICs)), insufficient targetd (or specific) therapies and the high toxicity of conventional chemotherapies. We have identified two gene families, FOXOs [foxo] and JNKs [junk] that are ideal targets for the design of novel anti-leukemia therapies because combined these genes are aberrantly active in the LIC populations of the majority of AMLs.