Determining the role of CUX1 in myeloid neoplasia

 描述(申请人提供)：仅在美国，今年就有超过50,000人被诊断出患有髓系肿瘤。7号染色体部分或全部缺失[-7/del(7q)]是初治急性髓系白血病常见的不良风险预后指标。携带-7/del(7q)基因的白血病对治疗耐药，这类患者的总体生存时间中位数不到一年。-7/del(7q)也出现在一半与治疗相关的髓系肿瘤中，这种肿瘤是先前癌症幸存者接受化疗和放射治疗的破坏性副作用。这项建议的长期目标是了解-7/del(7q)的分子异常，为这些患者开发新的治疗策略。我最近发现，转录因子基因CUX1位于染色体带7q的常见缺失片段内。我在体内模型中发现，CUX1是一个高度保守、单倍体不足的髓系肿瘤抑制基因。我发现了一个与CUX1相关的细胞周期基因信号，这表明CUX1通过调节增殖基因而发挥肿瘤抑制活性。这项建议的目的是确定CUX1调控的基因和途径，以及CUX1单倍体不足如何改变白血病的这些途径。根据初步数据，我推测CUX1通过抑制增殖和促进分化而抑制肿瘤生长。这一假设将通过创新的基因组分析和体内补充研究来验证。在目标1中，我将确定人造血干细胞中的CUX1转录靶点和原发急性髓系白血病样本中的异常CUX1靶点。我将使用这些数据来确定定义那些对单倍体不足的CUX1水平敏感的基因靶点的顺式调控逻辑。在目标2中，我将使用一种易于处理的在体模型，将人造血干细胞移植到免疫缺陷小鼠中，以确定CUX1肿瘤抑制活性的机制。这些实验将确定CUX1在髓系规范、生长和自我更新中的作用。这些研究将揭示那些由CUX1单倍体缺陷诱导的基因和途径。这些结果对未来R01水平的研究至关重要，以确定抑制CUX1下游效应器的药物。我提出了一个五年的职业发展计划，以确立我在骨髓癌基因组学领域的领先者地位。我的培训包括教学、机构资源，以及计算生物学、生物统计学和髓系生物学方面的监督研究。我已经组建了一支由一流的导师和顾问组成的团队来监督这次培训：凯文·怀特，基因组学和系统生物学领域的领导者，以及生物信息学、生物统计学和骨髓肿瘤生物学领域的国际公认的专家。通过在芝加哥大学丰富的学术环境中接受培训，我将发展成为一名转化型内科医生兼科学家，能够在血液系统恶性肿瘤的研究中弥合医学和下一代基因组学之间的鸿沟。芝加哥大学是髓系肿瘤和基因组学研究的长期世界领先者。

 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.