Genome Core

基因组核心

• 批准号: 10228884
• 负责人: Charles G. Mullighan
• 金额: $ 2.28万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228884
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult Acute Myeloblastic Leukemia; Affect; Biology; CRISPR library; CRISPR screen; Chemicals; Childhood Acute Myeloid Leukemia; Chimeric Proteins; Chromosomal Rearrangement; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; Custom; Data Analyses; Development; Disease; Elements; Experimental Models; Frequencies; Fusion Oncogene Proteins; Future; Gene Fusion; Gene Rearrangement; Genes; Genetic Screening; Genetic Transcription; Genome; Genomics; Goals; HOXA9 gene; Hematopoietic Neoplasms; Lead; Malignant - descriptor; Mediating; Molecular; Nuclear Pore Complex Proteins; Pathway interactions; Patients; Pharmacologic Substance; Pre-Clinical Model; Proteins; Regimen; Reporting; Research; Research Personnel; Scanning; Testing; Therapeutic; Validation; Work; density; effective therapy; gene panel; gene translocation; genome editing; genome-wide; innovation; insight; leukemia; leukemogenesis; new therapeutic target; novel; novel therapeutics; outcome forecast; pediatric patients; success; targeted treatment; therapeutic target

ABSTRACT NUP98 rearrangements are observed in up to 10% of the childhood acute myeloid leukemia (AML) and are associated with poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the NUP98-rearranged leukemias emphasize the need for novel regimens. Our central hypothesis is that NUP98-fusion oncoproteins harbor critical functional regions that are essential to their leukemogenetic potential. We also expect that NUP98-fusions will drive specific transcriptional networks, and provide potential vulnerabilities that can be exploited using CRISPR-mediated genome editing approach. We will test our hypothesis using multiple levels of CRISPR-mediated genetic screens covering genome-wide, target gene panel, and saturation protein scan. In collaboration with the Project 1 and Project 2 in this proposal, the Genome Editing Core will help provide critical insights into the molecular mechanisms by which NUP98- fusion oncoproteins lead to the development of leukemia. This work is innovative in that it will illuminate critical domains/motifs in NUP98-fusion oncoproteins, a particularly malignant disease that currently has no effective therapy. We expect that successful completion of this proposal will (1) establish a new genetic screen approach “saturation CRISPR protein scan” for a sub-protein level functional domain discovery, and (2) yield novel mechanistic information about the functional regions in the NUP98-fusion oncoproteins. The impact of this research will be of significance because (1) it provides novel therapeutic opportunities against the difficult-to-treat NUP98-rearranged leukemias, and (2) it will help identify novel functional elements in fusion oncoproteins and their associated pathways for future pharmaceutical targeting.

摘要 NUP98重排在高达10%的儿童急性髓性白血病中观察到 (AML)并且与不良预后相关。未满足的临床需求和缺乏 NUP98重排白血病的有效靶向治疗强调了对新的 养生法 我们的中心假设是NUP98融合癌蛋白具有关键的功能区域， 对他们的白血病潜能至关重要。我们还预计NUP98融合将推动 特定的转录网络，并提供潜在的漏洞，可以利用 CRISPR介导的基因组编辑方法。我们将使用多个水平来测试我们的假设 CRISPR介导的遗传筛选涵盖全基因组、靶基因组和饱和度 蛋白质扫描在本提案中，基因组与项目1和项目2合作， 编辑核心将有助于提供关键的见解，NUP98- 融合癌蛋白导致白血病的发展。 这项工作是创新的，因为它将阐明NUP98融合中的关键结构域/基序 癌蛋白，一种特别恶性的疾病，目前没有有效的治疗方法。我们预计 成功完成这项提案将（1）建立一种新的遗传筛查方法， 用于亚蛋白水平功能结构域发现的"饱和CRISPR蛋白扫描"，和（2） 产生关于NUP98-融合中的功能区域的新的机制信息 癌蛋白这项研究的影响将是有意义的，因为（1）它提供了新颖的 针对难治性NUP98重排白血病的治疗机会，和（2）它 将有助于识别融合癌蛋白及其相关通路中的新功能元件 用于未来的药物靶向。