Functional and Pharmacologic Investigation of the NUP98 Fusion Oncoprotein Interactome

NUP98 融合癌蛋白相互作用组的功能和药理学研究

基本信息

项目摘要

PROJECT SUMMARY Chromosomal translocations involving Nucleoporin 98 (NUP98) are observed in approximately 5% of pediatric acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcome, with approximately 35% 5 year overall survival. NUP98 rearrangements lead to expression of oncogenic chimeric gene fusions involving the intrinsically disordered, N-terminal region of NUP98 and the C-terminal region of one of over 30 identified partner genes. The partner genes commonly have domains with key functional properties, including homeodomain moieties (e.g. HOXA9) and roles in transcriptional regulation (e.g. NSD1, KDM5A). In complex with other machinery needed for gene regulation, NUP98 fusion oncoproteins (FOs) bind to the promoters of many developmental genes. This leads to changes in chromatin structure, increased expression of target genes, and aberrant hematopoietic self-renewal. Recent studies, including my own, have shown that the ability of NUP98 FOs to localize within the nucleus in membrane-less organelles, or “puncta” formed through liquid-liquid phase separation (LLPS), is necessary for transformation and deregulated gene expression phenotypes. Nevertheless, which proteins interact with NUP98 FOs in puncta and the importance of puncta formation for effective therapeutic targeting of NUP98-rearranged cells is not known. This research proposal seeks to identify the proteins found in NUP98 FO-associated puncta, uncover how puncta alter gene regulation, and determine if puncta disruption correlates with effective treatment of NUP98-rearranged cells. Aim 1 will examine the role of histone acetyltransferase (HAT) complex members, which my preliminary data identified as key NUP98 FO interacting proteins, in NUP98::KDM5A FO-driven cell transformation. I will perform CRISPR/Cas9 editing of HAT complex genes in hematopoietic stem and progenitor cells (HSPCs) from our Nup98::Kdm5a mouse model and study the in vitro and in vivo consequences of these alterations. I will also examine gene expression and chromatin remodeling in Nup98::Kdm5a HSPCs with and without HAT complex disruption. Aim 2 will determine whether effective therapeutic targeting of NUP98 FOs leads to puncta disruption. I will perform co-localization experiments for FO with proteins involved in nuclear transport and gene regulation. I will then pharmacologically inhibit these interacting proteins using available small molecule inhibitors and assess changes in puncta features and cell viability over time to determine if puncta disruption correlates with drug efficacy. In Aim 3, I will identify interacting proteins that are vulnerabilities in NUP98-rearranged cells and use pharmacologic inhibition of crucial interactors to identify how they are involved in cell transformation, gene regulation, and LLPS. Together, these studies will identify critical interacting proteins in leukemias bearing NUP98 gene fusions, examine how they contribute to leukemogenesis, and uncover how they might be targeted for therapeutic benefit.
项目摘要 在大约5%的儿童中观察到涉及核孔蛋白98(NUP 98)的染色体易位。 急性髓性白血病(AML),与治疗抵抗和不良结局相关, 约35%的5年总生存率。NUP 98重排导致致癌嵌合基因的表达 涉及NUP 98的固有无序的N-末端区域和NUP 98的C-末端区域的基因融合体, 超过30个已识别的伴侣基因。伴侣基因通常具有关键功能特性的结构域, 包括同源结构域部分(例如HOXA 9)和在转录调节中的作用(例如NSD 1、KDM 5A)。在 NUP 98融合癌蛋白(FO)与基因调控所需的其他机制复合, 许多发育基因的启动子。这导致染色质结构的变化, 靶基因和异常造血自我更新。最近的研究,包括我自己的研究,表明 NUP 98 FO定位于细胞核内无膜细胞器中的能力,或通过 液-液相分离(LLPS)是转化和解除基因表达调控所必需的 表型然而,在斑点中哪些蛋白质与NUP 98 FO相互作用以及斑点的重要性, NUP 98重排细胞的有效治疗靶向的形成是未知的。本研究提案 试图鉴定NUP 98 FO相关斑点中发现的蛋白质,揭示斑点如何改变基因调控, 并确定斑点破坏是否与NUP 98重排细胞的有效治疗相关。目标1将 研究组蛋白乙酰转移酶(HAT)复合物成员的作用,我的初步数据确定为 关键NUP 98 FO相互作用蛋白,在NUP 98::KDM 5A FO驱动的细胞转化中。我必坚定 CRISPR/Cas9编辑来自我们的造血干细胞和祖细胞(HSPC)中的HAT复合物基因 Nup 98::Kdm 5a小鼠模型,并研究这些改变的体外和体内后果。我也会 检查具有和不具有HAT复合物的Nup 98::Kdm 5a HSPC中的基因表达和染色质重塑 破坏目的2将确定NUP 98 FO的有效治疗靶向是否导致斑点破坏。 我将进行FO与参与核转运和基因调控的蛋白质的共定位实验。 然后,我将使用可用的小分子抑制剂来抑制这些相互作用的蛋白质, 评估斑点特征和细胞活力随时间的变化,以确定斑点破坏是否与 药效在目标3中,我将识别NUP 98重排细胞中的相互作用蛋白质, 使用关键相互作用物的药理学抑制,以确定它们如何参与细胞转化、基因 法规和LLPS。总之,这些研究将确定关键的相互作用蛋白质在白血病轴承 NUP 98基因融合,研究它们如何促进白血病发生,并揭示它们如何被靶向 以获得治疗效果。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Nicole Michmerhuizen其他文献

Nicole Michmerhuizen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Nicole Michmerhuizen', 18)}}的其他基金

Genetically faithful modeling of NUP98 rearrangement and co-alterations in acute myeloid leukemia
急性髓性白血病中 NUP98 重排和共同改变的遗传忠实模型
  • 批准号:
    10599975
  • 财政年份:
    2021
  • 资助金额:
    $ 14.1万
  • 项目类别:
Genetically faithful modeling of NUP98 rearrangement and co-alterations in acute myeloid leukemia
急性髓性白血病中 NUP98 重排和共同改变的遗传忠实模型
  • 批准号:
    10443579
  • 财政年份:
    2021
  • 资助金额:
    $ 14.1万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 14.1万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了