Determining the role of CUX1 in myeloid neoplasia

确定 CUX1 在骨髓瘤形成中的作用

• 批准号: 8820577
• 负责人: Megan McNerney
• 金额: $ 16.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820577
• 关键词: Acute Myelocytic Leukemia; Adverse effects; Bioinformatics; Biological Process; Biology; Biometry; Blood Cells; Cancer Survivor; Cell Differentiation process; ChIP-seq; Chicago; Chromosome Band; Chromosome abnormality; Chromosomes, Human, Pair 7; Computational Biology; DNA Binding; Data; Development Plans; Diagnosis; Differentiation and Growth; Diploidy; Disease; Dose; Drosophila genus; Drug Compounding; Environment; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Haploidy; Health; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; Human Genome; Immunodeficient Mouse; Lead; Logic; Malignant Neoplasms; Medicine; Mentors; Modeling; Molecular; Molecular Abnormality; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Neoplasms; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Prognostic Marker; Radiation; Research; Resistance; Resources; Risk; Role; Sampling; Scientist; Solid; Survivors; Systems Biology; Tars; Testing; Training; Transcription factor genes; Transcriptional Regulation; Transplantation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Umbilical Cord Blood; United States; Universities; Work; Xenograft procedure; base; cancer genomics; cancer therapy; career development; cdc Genes; cell growth; chemotherapy; chromosome 7q loss; high risk; human disease; improved; in vivo; in vivo Model; innovation; knock-down; leukemia; leukemogenesis; man; mouse model; new therapeutic target; next generation; outcome forecast; progenitor; programs; research study; response; self-renewal; small hairpin RNA; therapy development; transcription factor; transcriptome sequencing; treatment strategy; tumor growth; tumorigenesis; vif Genes

 DESCRIPTION (provided by applicant): Over 50,000 people will be diagnosed with a myeloid neoplasm this year in the U.S. alone. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common adverse-risk prognostic indicator in de novo acute myeloid leukemia. Leukemias with -7/del(7q) are resistant to treatment, and this subset of patients has a median over- all survival o less then a year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms, which arise as a devastating side-effect of chemotherapy and radiation in survivors of a prior cancer. The long-term goal of this proposal is to understand the molecular abnormalities of -7/del(7q) to develop new treatment strategies for these patients. I recently discovered that a transcription factor gene, CUX1, is within the commonly deleted segment of chromosome band 7q. I found that CUX1 is a highly conserved, haploinsufficient myeloid tumor suppressor gene using in vivo models. I identified a CUX1-associated cell cycle gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. The objective of this proposal is to identify the genes and pathways regulated by CUX1 and how CUX1 haploinsufficiency alters these path- ways in leukemia. Based on preliminary data, I hypothesize that CUX1 suppresses tumor growth by blocking proliferation and promoting differentiation. This hypothesis will be tested by innovative genomic analyses and complementary in vivo studies. In Aim 1, I will identify the CUX1 transcriptional targets in human hematopoietic stem cells and the aberrant CUX1 targets in primary acute myeloid leukemia samples. I will use this data to determine the cis-regulatory logic that defines those gene targets that are sensitive to haploinsufficient CUX1 levels. In Aim 2, I will identify the mechanism of CUX1 tumor suppressor activity, using a tractable, in vivo, model with human hematopoietic stem cells xenografted in immunodeficient mice. These experiments will establish the role for CUX1 in myeloid lineage specification, growth, and self-renewal. These studies will reveal those genes and pathways that are induced by CUX1 haploinsufficiency. These results are critical for future R01-level studies to identify drugs that inhibit downstream effectors of CUX1. I propose a five-year career development plan so as to establish myself as a leader in myeloid cancer genomics. My training is comprised of didactics, institutional resources, and supervised research in computational biology, biostatistics, and myeloid biology. I have assembled a first-class team of mentors and advisors to oversee this training: Kevin White, a leader in the field of genomics and systems biology, and internationally recognized experts in the fields of bioinformatics, biostatistics, myeloid neoplasi biology. With this training in the rich academic environment of the University of Chicago, a long-term world leader in the study of in myeloid neoplasia and genomics, I will develop into a translational physician-scientist who can bridge the gulf between medicine and next-generation genomics in the study of hematopoietic malignancies.

 描述（由适用提供）：仅在美国，今年将被诊断出50,000多人被诊断出患有髓样肿瘤。在从头急性髓样白血病中的常见不良风险预后指示器的零件或全部染色体的删除[-7/del（7q）]。 -7/del（7q）的白血病对治疗有抵抗力，并且该子集的中位数超过一年。 -7/del（7q）也发生在与治疗相关的髓样肿瘤的一半中，这是化学疗法的毁灭性副作用和先前癌症存活中的副作用。该提议的长期目标是了解-7/del（7q）的分子异常，以制定这些患者的新治疗策略。我最近发现，转录因子基因CUX1位于染色体带7Q的常见段中。我发现使用体内模型的Cux1是一种高度保守的单倍体骨髓抑制基因。我确定了与CUX1相关的细胞周期基因的特征，这表明CUX1通过控制增殖基因来执行肿瘤抑制活性。该提案的目的是确定由CUX1调​​节的基因和途径，以及Cux1单倍弹性如何改变白血病中的这些路径。根据初步数据，我假设CUX1通过阻止增殖和促进分化来抑制肿瘤的生长。该假设将通过体内研究中创新的基因组分析和完整性来检验。在AIM 1中，我将确定人造血干细胞中的CUX1转录靶标和原发性急性髓样白血病样品中的异常CUX1靶标。我将使用这些数据来确定定义对单倍弹性敏感的基因靶标的顺式调节逻辑。 CUX1水平。在AIM 2中，我将使用可与免疫缺陷小鼠中的人类造血干细胞异种移植的可拖动的体内模型一起确定CUX1肿瘤抑制活性的机理。这些实验将确定CUX1在髓样谱系规范，生长和自我更新中的作用。这些研究将揭示CUX1单倍弥补引起的那些基因和途径。这些结果对于未来的R01级研究至关重要，以鉴定抑制CUX1下游影响的药物。我提出了一个五年的职业发展计划，以确立自己的髓样癌基因组学领导者。我的培训完成了教学，机构资源以及计算生物学，生物统计学和髓样生物学的监督研究。我已经组建了一流的导师和顾问团队来监督这项培训：凯文·怀特（Kevin White）是基因组学和系统生物学领域的领导者，以及国际认可的生物信息学，生物统计学，生物统计学，髓样新肿瘤生物学领域的专家。借助芝加哥大学丰富的学术环境的培训，芝加哥大学是对髓样肿瘤和基因组学研究的长期世界领导者，我将发展成为一种翻译成的物理科学家，他可以在血肿恶性肿瘤研究中桥接医学和下一代基因组学之间的海湾。