Project 1

项目总结： NUP98重排急性白血病的儿童对传统治疗和 与疾病复发率高和总体结局差有关。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 融合癌蛋白的表达在一定程度上受到缺乏合适的模型系统的限制。不同类型 NUP98融合伙伴的存在，我们小组和其他人最近的工作表明，这些不同 融合与独特的临床、形态和基因组特征有关。例如，患有 NUP98-KDM5A融合通常表现为具有红系或巨核细胞特征的AML 可能存在相关的RB1功能缺失突变。相比之下，使用频率最高的NUP98-NSD1 NUP98融合，更常见的是与粒-单核细胞特征和共生的Flt3和/或 WT1突变。这些基因组和临床发现为研究这种基因奠定了强有力的科学前提。 不同NUP98融合对造血细胞的分子影响。我们假设不同的NUP98 癌蛋白将驱动特定转录网络的表达，部分是通过独特的合作 突变，并提供了可被表观遗传靶向治疗利用的潜在脆弱性。我们 将使用人类和人类基因工具的组合来测试我们的假设，具体目的如下 小鼠造血细胞；特异性目标1：确定不同NUP98对体外分子的影响 原代造血细胞的融合。具体目标2：建立基因组改变模式的联合模型 在患者体内观察建立新的NUP98重排白血病模型。具体目标3： 利用基因组编辑和小分子筛选来识别和开发NUP98的治疗脆弱性 白血病。拟议的研究不仅将阐明NUP98的转录和表观遗传影响 融合癌蛋白表达，并可能识别可利用的漏洞，但我们还将 建立多个鼠标和人体模型系统，包括PDX，它们将忠实地概括 在儿童中观察到的疾病。这将为该财团中的其他项目提供赠款和更大的 科学领域有必要的工具来最终开发靶向NUP98-融合的治疗方法 癌蛋白，最重要的是改善这些白血病儿童的长期预后。

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.