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%的实体肿瘤中观察到异常数量的染色体或非整倍体。在许多癌症中，这些额外染色体的积累是非随机的，有些染色体比其他染色体获得得更频繁。例如，8号染色体的获得与髓系疾病（包括急性髓系白血病（AML）和骨髓增生异常综合征（MDS））之间存在显著关联。尽管非整倍体和癌症之间的联系已经确立，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要障碍是缺乏具有不同核型的等基因细胞系。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马赛克三体，可以直接比较二倍体和非整倍体细胞，否则遗传上是相同的。我还获得了具有不同核型的诱导多能干细胞（iPS）。我计划利用这些细胞来研究8号三体在AML中的作用，以及识别具有倍体特异性致死率的小分子和基因。成功鉴定倍性特异性药物将代表一种新的癌症治疗方法。职业目标：我的长期职业目标是在儿科血液学/肿瘤科获得终身职位，成为一名内科科学家。K08奖将为我提供足够的时间进行高级培训，以实现这一职业目标。该研究计划是科学、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/Dana Farber癌症研究所儿科血液学/肿瘤学部门的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，目标是确保我获得成为一名成功的、专注于癌症生物学和临床儿科肿瘤学的独立研究者所需的专业知识。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、造血学和癌细胞生物学领域有许多专家研究人员。此外，波士顿儿童医院/达纳法伯癌症研究所的儿科血液学/肿瘤学部门在培养成功的内科科学家方面有着杰出的记录。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·戴利博士和纳撒尼尔·格雷博士组成，他们将指导我的研究和培训经历。