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
- 批准号:10724053
- 负责人:
- 金额:$ 14.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressBindingBioinformaticsBiological AssayBone Marrow TransplantationC-terminalCRISPR screenCRISPR/Cas technologyCell DeathCell NucleusCell SurvivalCellsChildhood Acute Myeloid LeukemiaChildhood LeukemiaChromatinChromatin StructureChromosomal RearrangementChromosomal translocationColony-forming unitsComplexDNA BindingDataData SetDevelopmental GeneDisadvantagedDiseaseEpigenetic ProcessFusion Oncogene ProteinsGene ExpressionGene Expression ProfileGene Expression RegulationGene FusionGenesGoalsGuide RNAHOXA9 geneHematopoieticHematopoietic stem cellsHistone AcetylationImmunoprecipitationIn VitroInvestigationLeadLibrariesLiquid substanceLysineMLL geneMalignant - descriptorMalignant NeoplasmsMass Spectrum AnalysisMediatingMediatorMembraneModelingMusN-terminalNuclear Pore Complex ProteinsOncogene DeregulationOncogenicOrganellesOutcomePatient-Focused OutcomesPharmacologyPhasePhenotypePropertyProteinsReaderRecurrenceResearchResearch ProposalsRoleSaint Jude Children&aposs Research HospitalScientistTestingTherapeuticTherapeutic InterventionTimeTrainingTranscriptional RegulationValidationcareercell growthcell transformationchimeric genechromatin remodelingdesigndrug efficacyeffective therapyepigenomicsexperimental studyexportin 1 proteinfitnessfunctional genomicshigh riskhistone acetyltransferasehomeodomainin vivoleukemialeukemogenesismembermouse modelnovelnovel therapeutic interventionnucleocytoplasmic transportpharmacologicpost-doctoral trainingpre-doctoralpromoterquantitative imagingself-renewalsmall moleculesmall molecule inhibitorstem-like cellstructural biologytargeted treatmenttherapeutic targettherapeutically effectivetherapy resistant
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.
项目概要
在大约 5% 的儿科患者中观察到涉及核孔蛋白 98 (NUP98) 的染色体易位
急性髓系白血病 (AML),与治疗耐药和不良预后相关,
5 年总生存率约为 35%。 NUP98 重排导致致癌嵌合体的表达
涉及本质上无序的 NUP98 N 端区域和 NUP98 的 C 端区域的基因融合
超过 30 个已识别的伙伴基因。伴侣基因通常具有具有关键功能特性的域,
包括同源结构域部分(例如 HOXA9)和转录调控中的作用(例如 NSD1、KDM5A)。在
NUP98 融合癌蛋白 (FO) 与基因调控所需的其他机制形成复合体,与
许多发育基因的启动子。这导致染色质结构的变化,增加表达
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,
NUP98 FO 定位在无膜细胞器核内的能力,或通过形成的“点”
液-液相分离(LLPS)对于转化和解除基因表达调控是必要的
表型。然而,哪些蛋白质与点中的 NUP98 FO 相互作用以及点的重要性
NUP98 重排细胞的有效治疗靶向的形成尚不清楚。本研究提案
试图鉴定 NUP98 FO 相关 puncta 中发现的蛋白质,揭示 puncta 如何改变基因调控,
并确定泪点破坏是否与 NUP98 重排细胞的有效治疗相关。目标1将
检查组蛋白乙酰转移酶 (HAT) 复合体成员的作用,我的初步数据将其确定为
NUP98::KDM5A FO 驱动的细胞转化中的关键 NUP98 FO 相互作用蛋白。我将表演
对我们的造血干细胞和祖细胞 (HSPC) 中的 HAT 复合体基因进行 CRISPR/Cas9 编辑
Nup98::Kdm5a 小鼠模型并研究这些改变的体外和体内后果。我也会
检查带有和不带有 HAT 复合物的 Nup98::Kdm5a HSPC 中的基因表达和染色质重塑
扰乱。目标 2 将确定 NUP98 FO 的有效治疗靶向是否会导致泪点破坏。
我将对 FO 与参与核运输和基因调控的蛋白质进行共定位实验。
然后我将使用可用的小分子抑制剂从药理学上抑制这些相互作用的蛋白质
评估泪点特征和细胞活力随时间的变化,以确定泪点破坏是否与
药物功效。在目标 3 中,我将识别 NUP98 重排细胞中存在漏洞的相互作用蛋白,以及
使用关键相互作用物的药理抑制来确定它们如何参与细胞转化、基因
监管和 LLPS。总之,这些研究将确定白血病携带中关键的相互作用蛋白
NUP98 基因融合,检查它们如何促进白血病发生,并揭示它们如何被靶向
为了治疗效果。
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)
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Nicole Michmerhuizen其他文献
Nicole Michmerhuizen的其他文献
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{{ 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:
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