Trisomy 8 in hematopoiesis and myeloid leukemia

造血和髓性白血病中的 8 三体性

• 批准号: 8164245
• 负责人: David J Gordon
• 金额: $ 17.01万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164245
• 关键词: AML1-ETO fusion protein; Abnormal Karyotype; Acute Myelocytic Leukemia; Advisory Committees; Affect; Aneuploid Cells; Aneuploidy; Apoptotic; Area; Award; Biological Models; Boston; Cancer Biology; Cell Line; Cell Separation; Cells; Cellular biology; Childhood Acute Lymphocytic Leukemia; Chromosomal Instability; Chromosome Transfer; Chromosomes; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Clinical; Critiques; Dana-Farber Cancer Institute; Dependency; Development; Development Plans; Diploid Cells; Diploidy; Disease; Drops; Dysmyelopoietic Syndromes; Employee Strikes; Ensure; Environment; Ewings sarcoma; Exhibits; Experimental Models; Frequencies; Gene Dosage; Genes; Genetic Drift; Goals; Gray unit of radiation dose; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Human; Individual; Link; MLLT3 gene; Malignant Neoplasms; Mediating; Mentors; Methods; Myelogenous; Myeloid Leukemia; Oncogenes; Pathogenesis; Pediatric Hematology/Oncology; Pediatric Hospitals; Pediatric Oncology; Pharmaceutical Preparations; Phenotype; Physicians; Ploidies; Positioning Attribute; Research; Research Personnel; Research Proposals; Research Training; Role; Scientist; Solid Neoplasm; Structure; Tetrasomy; Time; Training; Trisomy; Trisomy 8; Universities; Work; Writing; Yeasts; bcr-abl Fusion Proteins; cancer cell; cancer therapy; career; career development; chromosome 8 gain; experience; genetic manipulation; induced pluripotent stem cell; innovation; leukemia; leukemogenesis; meetings; neoplastic cell; novel therapeutic intervention; programs; small hairpin RNA; small molecule; small molecule libraries; stem cell biology; tumor

DESCRIPTION (provided by applicant): An abnormal number of chromosomes, or aneuploidy, is observed in 70% of hematologic malignancies and 95% of solid tumors. The accumulation of these extra chromosomes is nonrandom in many cancers, with some chromosomes being acquired more frequently than others. For example, there is a significant association between the gain of chromosome 8 and myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although this link between aneuploidy and cancer is well-established, the mechanistic details are still poorly understood. A significant barrier to investigating questions related to aneuploidy has been a lack of isogenic cell lines with different karyotypes. Recently, I developed two complementary approaches, using microcell mediated chromosome transfer and mosaic trisomy, that enable a direct comparison of diploid and aneuploid cells that are otherwise genetically identical. I also generated induced pluripotent stem cells (iPS) with different karyotypes. I plan to use these cells to investigate the role of trisomy 8 in AML, as well as to identify small molecules and genes which exhibit ploidy- specific lethality. The successful identification of ploidy-specific drugs would represent a novel therapeutic approach in cancer. Candidate Career Goals: My long-term career objective is to obtain a tenure-track position as a physician-scientist in a pediatric hematology/oncology department. The K08 award will provide the protected time I need for advanced training in order to achieve this career goal. This research proposal is part of a structured plan with scientific, technical, clinical, and career development components. The research will performed under the guidance of Dr. David Pellman in the Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on cancer biology and clinical pediatric oncology. Environment: The Dana-Farber Cancer Institute (DFCI), Children's Hospital Boston and Harvard University are internationally recognized research programs with a number of expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. Furthermore, The Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute has a distinguished record of training successful physician scientists. I have assembled an excellent mentoring and advisory committee, consisting of Dr. David Pellman, Dr. Scott Armstrong, Dr. George Daley and Dr. Nathanael Gray, that will guide my research and training experiences. PUBLIC HEALTH RELEVANCE: Many cancer cells have an abnormal number of chromosomes. This proposal describes an innovative approach to study the effect of extra chromosomes on the development of leukemia. The long-term goals of this project are to determine how cancers arise and to develop new anti- cancer therapies that specifically target cells with extra chromosomes. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

描述（由申请人提供）：在 70% 的血液恶性肿瘤和 95% 的实体瘤中观察到染色体数量异常或非整倍性。在许多癌症中，这些额外染色体的积累是非随机的，某些染色体比其他染色体更频繁地获得。例如，第 8 号染色体的获得与骨髓疾病（包括急性髓系白血病 (AML) 和骨髓增生异常综合征 (MDS)）之间存在显着关联。尽管非整倍体与癌症之间的联系已得到充分证实，但其机制细节仍然知之甚少。研究与非整倍性相关的问题的一个重大障碍是缺乏具有不同核型的同基因细胞系。最近，我开发了两种互补的方法，使用微细胞介导的染色体转移和嵌合三体，可以直接比较在其他方面遗传相同的二倍体和非整倍体细胞。我还生成了具有不同核型的诱导多能干细胞（iPS）。我计划使用这些细胞来研究 8 三体在 AML 中的作用，并鉴定表现出倍性特异性致死性的小分子和基因。倍性特异性药物的成功鉴定将代表一种新的癌症治疗方法。候选人职业目标：我的长期职业目标是获得儿科血液学/肿瘤科医师科学家的终身职位。 K08 奖项将为我提供高级培训所需的受保护时间，以实现这一职业目标。该研究提案是包含科学、技术、临床和职业发展组成部分的结构化计划的一部分。该研究将在波士顿儿童医院/达纳法伯癌症研究所儿科血液学/肿瘤科 David Pellman 博士的指导下进行。职业发展计划建立在我之前的研究和临床经验的基础上，目的是确保我获得成为一名成功的独立研究者所需的专业知识，重点关注癌症生物学和临床儿科肿瘤学。环境：丹娜—法伯癌症研究所 (DFCI)、波士顿儿童医院和哈佛大学是国际公认的研究项目，在干细胞生物学、造血和癌细胞生物学领域拥有众多专家研究人员。此外，波士顿儿童医院/达纳法伯癌症研究所的儿科血液学/肿瘤学部门在培训成功的医师科学家方面拥有杰出的记录。我组建了一个优秀的指导和咨询委员会，由大卫·佩尔曼博士、斯科特·阿姆斯特朗博士、乔治·戴利博士和纳撒内尔·格雷博士组成，他们将指导我的研究和培训经历。 公共卫生相关性：许多癌细胞的染色体数量异常。该提案描述了一种研究额外染色体对白血病发展影响的创新方法。该项目的长期目标是确定癌症是如何产生的，并开发专门针对具有额外染色体的细胞的新抗癌疗法。 下面的“评论”部分以基本上未经编辑的形式提供了个人评论者的书面评论和标准分数。请注意，这些批评和标准分数是在会议之前准备的，在审查会议上进行任何讨论后可能不会进行修改。上面的“讨论简历和摘要”部分总结了委员会的最终意见。