Unexpected mechanism underlying mislocalization of thrombocytopenia-associated ETV6 point mutation
血小板减少症相关 ETV6 点突变错误定位的意外机制
基本信息
- 批准号:10605685
- 负责人:
- 金额:$ 3.88万
- 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:2023-01-31 至 2026-01-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAmino AcidsAnimal ModelBindingBioinformaticsBiological ModelsBlood PlateletsCell MaintenanceCell NucleusCell modelCellsChemicalsChildhood Precursor B Lymphoblastic LeukemiaChronic Myelomonocytic LeukemiaClinVarCytoplasmDNA BindingDNA Binding DomainDataDevelopmentDiseaseDysmyelopoietic SyndromesETV6 geneExhibitsFamilyFunctional ImagingFunctional disorderGeneticGenetic MarkersGenetic VariationGerm-Line MutationGoalsHematologic NeoplasmsHematopoieticHeterozygoteHourIn VitroInduced MutationInheritedKnockout MiceMalignant NeoplasmsMammalian CellMapsMediatingMegakaryocytesMissense MutationMutateMutationNuclearNuclear ExportPenetrancePeripheralPlatelet Count measurementPoint MutationProductionProteinsRUNX1 geneRecurrenceRiskSignal TransductionSomatic MutationTertiary Protein StructureThrombocytopeniaThrombopoiesisTranscription RepressorTransgenic MiceVariantWorkbiophysical techniquesconditional knockoutexportin 1 proteingene repressiongenetic approachhuman diseaseinhibitorleptomycin Bleukemiametermouse modelmutantmutation carriernovelnovel markerprotein functionprotein reconstitutionpublic databasestem cellstooltranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
ETV6 is a transcriptional repressor involved inhematopoietic stem cell maintenance and terminal differentiation
of megakaryocytes. ETV6 conditional knockout mice demonstrate a marked decrease in peripheral platelet
counts and a compensatory increase in immature megakaryocytes. In concordance with these findings, in
recent years, a number of germline mutations in ETV6 that result in mislocalization of the protein from the
nucleus to the cytoplasm have been associated with inherited thrombocytopenia. Carriers of these mutations
are also at an increased risk of hematologic malignancies as ~30% have gone on to develop myelodysplastic
syndrome or leukemia. Most of these germline mutations are found in the DNA-binding domain (DBD) of ETV6.
Functional studies of these DBD mutations demonstrate a loss of DNA-binding capacity in vitro and a loss of
transcriptional repression in cells. However, one mutation, the Pro214Leu missense mutation identified in 5
families thus far, occurs in the long intrinsically disordered central domain of ETV6. It too demonstrates a loss
of transcriptional repression in vitro, but the mechanism explaining this loss has not yet been established.
Preliminary data I have gathered demonstrates that this Pro214Leu missense mutation creates a de novo
nuclear export signal (NES) leading to exportin 1 (XPO1) mediated nuclear export. This constitutes the first
described instance of a point mutation creating a de novo NES. We intend to develop cellular and animal
model systems to probe the effects of this unexpected disease mechanism on thrombopoiesis. We are
developing a homologous ETV6 P214L transgenic mouse line will validate its suitability as an animal model of
ETV6-related thrombocytopenia. This will allow us to use genetic and chemical tools to study the effects of
ETV6 P214L nuclear relocalization on megakaryocyte and platelet development. Lastly, a preliminary
bioinformatics search utilizing ClinVar, a publicly available database of genetic variation, and an NES
prediction server has yielded additional candidate mutations that may also create de novo NESs. We intend to
show that missense mutation dependent nuclear export is a general mechanism of disease, and
characterization of candidate NESs may yield novel biomarkers of disease.
项目总结/文摘
项目成果
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Michael R McConville其他文献
Michael R McConville的其他文献
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