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

基本信息

批准号：
8300569
负责人：
Stephen Matthew Sykes
金额：
$ 14.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2012-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300569
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 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

项目摘要

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.

描述（由申请人提供）：AML 是一种由未成熟白细胞不受控制的扩张引起的血癌。 AML 患者的死亡率极高，只有 23% 的患者存活超过 5 年。这种不良的预后是由于白血病复发率高以及当前疗法的无效性和毒性造成的。虽然这些令人震惊的现实需要开发更有效的 AML 化疗，但两个主要因素使这一概念变得复杂。首先，一小部分但独特的白血病细胞（称为白血病起始细胞或 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遗传异常，这限制了设计广谱抗AML药物的能力。因此，识别和针对 LIC 中特异发现的常见分子不规则性是开发成功的广泛 AML 疗法的关键基础。使用源自大型人类 AML 样本集的基因表达数据集，我们发现 FOXO 基因家族在约 40% 的 AML 病例中被不当激活。使用 AML 小鼠模型，我们还发现 FOXO 是 LIC 的关键调节因子。进一步调查显示，大约 60% 的白血病样本对 FOXO 抑制具有抵抗力。那些对 FOXO 不敏感的细胞存在另一种途径的异常，即 JNK 基因家族。使用抑制 JNK 酶的药物来抑制 FOXO 和 JNK，甚至可以显着杀死耐药的癌细胞。我们现在的目标是确定 FOXO 和 JNK 途径的下游效应器，这些效应器允许这些基因促进白血病发生。具体来说，我们将研究 FOXO 和 JNK 通路的操纵如何影响癌基因 c-JUN 和连环蛋白的活性。此外，我们想要评估这些途径的药理学开发是否为 AML 的治疗提供了原则上经过验证的策略。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 AML 细胞生长和 LIC 功能来实现这一目标。我们相信，这些拟议的实验完全符合国家癌症研究所的使命，即发现人类癌症的新分子特征，从而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 名因此死亡。 AML 的高死亡率是疾病频繁复发（由称为白血病起始细胞 (LIC) 的稀有细胞引起）、靶向（或特异性）治疗不足以及传统化疗的高毒性的累积结果。我们已经确定了两个基因家族，FOXOs [foxo] 和 JNKs [junk]，它们是设计新型抗白血病疗法的理想靶标，因为这些基因组合在大多数 AML 的 LIC 群体中异常活跃。