Project 1

项目1

• 批准号: 10900856
• 负责人: Charles G. Mullighan
• 金额: $ 16.15万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10900856
• 关键词: ATAC-seq; Acute leukemia; Adolescent; Biological; Biological Assay; Biological Models; Biology; Bromodomain; CRISPR/Cas technology; Cell Line; Cells; ChIP-seq; Chemicals; Chemistry; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chimeric Proteins; Chromatin; Chromosomal Rearrangement; Classification; Clinical; Collaborations; Coupled; DNA Sequence Alteration; Data; Development; Disease; Effectiveness; Epigenetic Process; Erythroid; Experimental Models; FLT3 gene; Fusion Oncogene Proteins; Gene Fusion; Gene Rearrangement; Genes; Genetic; Genetic Transcription; Genomics; Goals; Grant; HOXA9 gene; Hematopoietic; Hematopoietic stem cells; Homeobox; Human; In Vitro; Inferior; Institution; Lead; Megakaryocytes; Modeling; Molecular; Morphology; Mus; Mutation; Nuclear Pore Complex Proteins; Oncoproteins; Outcome; Patients; Pattern; Pre-Clinical Model; Preclinical Testing; Prognosis; Proteins; RB1 gene; Recurrent disease; Research Personnel; Role; Sampling; Testing; Therapeutic; Transplantation; WT1 gene; Work; chemotherapeutic agent; chemotherapy; clinical phenotype; conventional therapy; genome editing; genome-wide; high risk; human cord blood CD34+ cell; human model; improved; in vivo; in vivo Model; inhibitor; insight; lentivirally transduced; leukemia; loss of function; loss of function mutation; mouse model; new therapeutic target; novel; response; screening; small molecule; somatic cell gene editing; success; targeted treatment; therapeutic target; tool; transcriptome sequencing; tumor

PROJECT SUMMARY: Children with NUP98-rearranged acute leukemias demonstrate a poor response to conventional therapy and are associated a high rate of relapsed disease and poor overall outcome. These fusions account for approximately 10% of children with AML, yet our overall understanding of the molecular consequences of fusion oncoprotein expression has been limited in part by a paucity of suitable model systems. Different types of NUP98 fusion partners exist and recent work from our group and others have shown that these different fusions are associated with unique clinical, morphologic and genomic features. For example, children with a NUP98-KDM5A fusion commonly present with an AML with either erythroid or megakaryoblastic features and can have an associated RB1 loss of function mutation. In contrast, NUP98-NSD1, which is the most frequent NUP98 fusion, more commonly is associated with myelomonocytic features and co-occurring FLT3 and/or WT1 mutations. These genomic and clinical findings establish a strong scientific premise to investigate the molecular impact of different NUP98 fusions in hematopoietic cells. We hypothesize that different NUP98 oncoproteins will drive the expression of specific transcriptional networks, in part through unique cooperating mutations, and provide potential vulnerabilities that can be exploited by epigenetic targeted therapies. We will test our hypothesis with the following specific aims using a combination of genetic tools in human and mouse hematopoietic cells; Specific Aim 1: To determine the in vitro molecular impact of different NUP98 fusions in primary hematopoietic cells. Specific Aim 2: To co-model patterns of genomic alterations observed in patients to establish new in vivo models of NUP98-rearranged leukemias. Specific Aim 3: To utilize genome editing and small molecule screens to identify and exploit therapeutic vulnerabilities for NUP98 leukemias. Not only will the proposed studies elucidate the transcriptional and epigenetic impact of NUP98 fusion oncoprotein expression and potentially identify vulnerabilities that can exploited, but we will also establish multiple mouse and human model systems, including PDX, that will faithfully recapitulate the diseases observed in children. This will provide both the other Projects in this consortium grant and greater the scientific field with necessary tools to ultimately develop therapeutic approaches to target NUP98-fusion oncoproteins and most importantly to improve the long-term outcome of children with these leukemias.

项目概要： 患有NUP 98重排的急性白血病的儿童对常规治疗的反应较差， 与疾病复发率高和总体预后差相关。这些融合解释了 大约10%的AML儿童，但我们对AML的分子后果的总体理解 融合癌蛋白的表达部分受到缺乏合适模型系统的限制。不同类型 NUP 98融合伴侣的存在，我们小组和其他人最近的工作表明，这些不同的 融合体与独特的临床、形态学和基因组特征相关。例如，患有 NUP 98-KDM 5A融合通常与具有红系或巨核母细胞特征的AML一起出现， 可能有相关的RB 1功能缺失突变。相比之下，NUP 98-NSD 1，其是最常见的 NUP 98融合，更常见地与骨髓单核细胞特征和共发生的FLT 3和/或FLT 3/FLT 3融合相关。 WT 1突变。这些基因组学和临床发现为研究 不同NUP 98融合体在造血细胞中的分子影响。我们假设不同的NUP 98 癌蛋白将驱动特定转录网络的表达，部分是通过独特的协同作用， 突变，并提供可被表观遗传靶向疗法利用的潜在脆弱性。我们 将测试我们的假设与以下具体目标使用的组合遗传工具在人类和 小鼠造血细胞;具体目的1：确定不同NUP 98的体外分子影响 在原代造血细胞中的融合。具体目标2：共同建模基因组改变模式 在患者中观察到建立NUP 98重排白血病的新体内模型。具体目标3： 利用基因组编辑和小分子筛选来识别和利用NUP 98的治疗漏洞 白血病这些研究不仅将阐明NUP 98的转录和表观遗传影响， 融合癌蛋白的表达，并可能确定可以利用的漏洞，但我们也将 建立多个小鼠和人类模型系统，包括PDX，这将忠实地概括 在儿童中观察到的疾病。这将为该财团赠款中的其他项目提供更多资金， 科学领域与必要的工具，最终开发治疗方法，以靶向NUP 98融合 癌蛋白，最重要的是改善这些白血病儿童的长期预后。