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.
项目总结
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)
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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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