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.

抽象的 在多达10％的儿童急性髓样白血病中观察到NUP98重排 （AML），并与预后不良有关。未满足的临床需求和缺乏 对NUP98重新培养白血病的有效靶向疗法强调了新型的需求 方案。 我们的中心假设是Nup98融合癌蛋白具有关键功能区域 对于它们的白血病潜力至关重要。我们还希望NUP98-融合会驱动 特定的转录网络，并提供可以使用的潜在漏洞 CRISPR介导的基因组编辑方法。我们将使用多个级别检验我们的假设 CRISPR介导的遗传筛选涵盖全基因组，靶基因面板和满意度 蛋白质扫描。在本提案中与项目1和项目2合作，基因组 编辑核心将有助于提供对NUP98-的分子机制的关键见解。 融合癌蛋白导致白血病的发展。 这项工作具有创新性，因为它将照亮NUP98融合中的关键域/图案 癌蛋白，一种特别恶性疾病，目前尚无有效的治疗。我们期望 该提案的成功完成将（1）建立新的遗传筛选方法 亚蛋白水平功能域发现的“饱和CRISPR蛋白扫描”和（2） 产生有关NUP98融合中功能区域的新机械信息 癌蛋白。这项研究的影响将具有重要意义，因为（1）它提供了新颖的 反对难以治疗的NUP98重新制定的白血病的治疗机会，（2） 将有助于识别融合癌蛋白及其相关途径中的新功能元素 用于未来的药物靶向。