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: 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
• 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

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患者的死亡率非常高，只有23%的患者存活超过5年。这种不良预后是由于白血病复发率高，以及目前治疗的无效和毒性。虽然这些令人担忧的现实要求开发更有效的AML化疗，但这一概念因两个主要因素而变得复杂。首先，一小部分白血病细胞（称为白血病起始细胞或LICs）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，识别和靶向在lic中发现的常见分子不规则性是开发成功的广泛AML治疗的关键基础。