Trisomy 8 in hematopoiesis and myeloid leukemia

造血和髓性白血病中的 8 三体性

• 批准号: 8295002
• 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/8295002
• 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; MLL-AF9; 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.

描述（由申请人提供）：在70％的血液恶性肿瘤和95％的实体瘤中观察到异常数量的染色体或非整倍性。在许多癌症中，这些额外的染色体的积累是非随机的，而某些染色体比其他染色体更频繁地获取。例如，染色体8染色体和髓样疾病（包括急性髓样白血病（AML））和骨髓异常综合征（MDS）之间存在显着关联。尽管非整倍性与癌症之间的这种联系已经建立了良好的知识，但机械细节仍然鲜为人知。研究与非整倍性有关的问题的重要障碍是缺乏不同的核型的等源细胞系。最近，我使用了Microcell介导的染色体转移和镶嵌三体膜开发了两种互补方法，从而可以直接比较二倍体和非整倍体细胞，这些细胞原本相同。我还产生了具有不同核型的诱导多能干细胞（IP）。我计划使用这些细胞研究三体术在AML中的作用，并鉴定出表现出倍形性致死性的小分子和基因。成功鉴定倍倍特异性药物将代表癌症的一种新型治疗方法。候选职业目标：我的长期职业目标是在儿科血液学/肿瘤科中担任医师科学家的终身任职地位。 K08奖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。该研究建议是具有科学，技术，临床和职业发展组成部分的结构化计划的一部分。这项研究将在波士顿儿童医院/达娜·法伯癌症研究所的儿童医院小儿血液学/肿瘤学系的指导下进行。职业发展计划以我先前的研究和临床经验为基础，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，专注于癌症生物学和临床小儿肿瘤学。环境：Dana-Farber癌症研究所（DFCI），波士顿儿童医院和哈佛大学是国际认可的研究计划，在干细胞生物学，造血和癌细胞生物学领域的许多专家研究人员中。此外，波士顿儿童医院/达娜·法伯癌症研究所的儿科血液学/肿瘤学系有培训成功的医师科学家的杰出记录。我组建了一个出色的指导和咨询委员会，由戴维·佩尔曼（David Pellman）博士，斯科特·阿姆斯特朗（Scott Armstrong）博士，乔治·戴利（George Daley）博士和纳塔奈尔·格雷（Nathanael Gray）博士组成，这将指导我的研究和培训经验。