Novel Spliceosomal Defects in Myelodysplastic Syndromes
骨髓增生异常综合征中的新型剪接体缺陷
基本信息
- 批准号:9335972
- 负责人:
- 金额:$ 60.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos Splice Site5q31AffectAllelesAlternative SplicingApoptosisBiological AssayCD34 geneCell LineCell modelCellsChromosome abnormalityClinicalClustered Regularly Interspaced Short Palindromic RepeatsCodeDataDefectDevelopmentDifferentiation and GrowthDiseaseDysmyelopoietic SyndromesEngineeringEventEvolutionFailureFunctional disorderGene ExpressionGene ProteinsGene TargetingGenesGenomicsGoalsHematopoiesisHeterogeneityHumanHuman EngineeringIn VitroIneffective HematopoiesisKnock-inKnock-outLesionLinkMarrowMediatingMessenger RNAModelingMolecularMusMutateMutationMyeloproliferative diseaseOligonucleotidesOncogenicOutcomePathogenesisPathogenicityPathway interactionsPatientsPatternPhenocopyPhenotypePlayProtein IsoformsProteinsPublishingRNARNA BindingRNA HelicaseRNA ProcessingRNA SplicingRegulationRoleSRSF2 geneSamplingSiteSomatic MutationSpecificitySpliced GenesSpliceosomesSystemTechnologyTestingTumor Suppressor GenesXenograft procedurebaseclinical phenotypecrosslinking and immunoprecipitation sequencingcytopeniaexperimental studygenetic analysisimprovedin vitro testingin vivoinduced pluripotent stem cellknock-downleukemialeukemogenesisloss of function mutationmRNA Expressionmutantnew therapeutic targetnoveloverexpressionpublic health relevancesmall hairpin RNAtranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are characterized by dysplastic ineffective hematopoiesis, cytopenias and leukemic evolution. New technological advances have allowed for improved analysis of genetic somatic defects. Among newly identified lesions, several spliceosomal factor genes were frequently found to be mutated. These included common mutations in SF3B1, ZRSR2, SRSF2 and U2AF1 as well as less prevalent mutations in PRPF8, DDX41 and others. This discovery has led to the hypothesis that alterations in the pattern of splicing of target genes plays a major role in the establishment or progression of MDS. This proposal focuses on our recent identification of inactivating mutations in the LUC7L2 gene and frequent haploinsufficiency due to deletions at 7q34 involving the LUC7L2 locus. Clinical analysis shows that deletion/low expression of LUC7L2 is associated with poor outcome. Recently published data show that LUC7L2 can reverse defective differentiation in del7q human iPS cells. Preliminary data shows that engineered human iPS cells with LUC7L2 haploinsufficiency have defective differentiation similar to del7q. LUC7L2 is thought to regulate 5' splice site choice during splicing. RNA-Seq results suggest that multiple genes have altered splicing patterns due to defects in LUC7L2. Our proposal is based on the hypothesis that mutations and/or haploinsufficiency of spliceosomal proteins such as LUC7L2 leads to specific types of missplicing of specific or distinct combinations of TSG and ultimately, that spliceosomal defects may phenocopy consequences of other molecular defects affecting specific genes or pathways. The goals of the proposal are to understand the consequences of LUC7L2 deficiency in relation to the development and progression of MDS. The effects of haploinsufficiency in primary cells and in engineered shRNA knockdown cells and LUC7L2 knock out iPS cells will be investigated in culture including effects on proliferation, differentiaion and apoptosis. We will perform splicing analysis using deep RNA sequencing to characterize splicing dysfunction and its consequences on mRNA expression to determine downstream mechanisms and target genes. To identify direct splicing targets, RNA splicing assays will be performed in vivo and in vitro with LUC7L2 knocked down and mutant knock-in cells. RNA CLIP-Seq and direct RNA binding analyses will be used to define the in vivo RNA substrates of LUC7L2 action. Finally, we will examine the roles of candidate downstream genes whose splicing and expression is altered in LUC7L2 defective cells and patient samples. Preliminary data suggests that LUC7L2 levels regulate the splicing of several downstream genes including SMAD5. Using engineered cell lines and/or patient samples, we will test the roles of the missplicing events by inducing or inhibiting alternative splice sites using antisense morpholino oligonucleotides. While in vitro testing will examine growth and differentiation, in vivo experiments will be carried out in NSG mouse xenografts containing knockdown, knock out or primary MDS cells haploinsufficient in LUC7L2.
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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Jaroslaw P Maciejewski其他文献
Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors
阵发性夜间血红蛋白尿症的口服依他西普单药治疗:抗 C5 治疗患者的开放标签、随机、3 期 APPLY-PNH 试验和先前未接受补体抑制剂治疗的患者的开放标签、单臂、3 期 APOINT-PNH 试验的最终 48 周结果
- DOI:
10.1016/s2352-3026(25)00081-x - 发表时间:
2025-06-01 - 期刊:
- 影响因子:17.700
- 作者:
Antonio M Risitano;Austin G Kulasekararaj;Phillip Scheinberg;Alexander Röth;Bing Han;Jaroslaw P Maciejewski;Yasutaka Ueda;Carlos M de Castro;Eros Di Bona;Rong Fu;Li Zhang;Morag Griffin;Saskia M C Langemeijer;Jens Panse;Hubert Schrezenmeier;Wilma Barcellini;Vitor A Q Mauad;Philippe Schafhausen;Suzanne Tavitian;Eloise Beggiato;Régis Peffault de Latour - 通讯作者:
Régis Peffault de Latour
Homeobox Transcription Factor HHEX Promotes Myeloid Leukemia In Cooperation With Mutant ASXL1
同源框转录因子 HHEX 与突变体 ASXL1 合作促进粒细胞白血病
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
竹田玲奈;浅田修平;朴聖俊;横山明彦;金井昭教;Valeria Visconte;Courtney Hershberger;林康孝;米澤大志;田村萌;福山朋房;松本明子;山崎智;中井謙太;稲葉俊哉;柴田龍弘;井上大地;本田浩章;合山進;Jaroslaw P Maciejewski;北村俊雄 - 通讯作者:
北村俊雄
Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.
口服 Iptacopan 单药治疗阵发性睡眠性血红蛋白尿。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:158.5
- 作者:
Régis Peffault de Latour;Alexander Röth;Austin G. Kulasekararaj;Bing Han;Phillip Scheinberg;Jaroslaw P Maciejewski;Yasutaka Ueda;Carlos de Castro;Eros Di Bona;Rong Fu;Li Zhang;Morag Griffin;Saskia M C Langemeijer;Jens Panse;Hubert Schrezenmeier;Wilma Barcellini;V. A. Mauad;Philippe Schafhausen;Suzanne Tavitian;Eloise Beggiato;Lee Ping Chew;Anna Gaya;Wei;Jun Ho Jang;Toshio Kitawaki;Abdullah Kutlar;Rosario Notaro;Vinod Pullarkat;Jörg Schubert;Louis Terriou;Michihiro Uchiyama;Lily Wong Lee Lee;E. Yap;F. Sicre de Fontbrune;Luana Marano;F. Alashkar;Shreyans Gandhi;Roochi Trikha;Chen Yang;Hui Liu;Richard J. Kelly;B. Höchsmann;Cécile Kerloeguen;Partha Banerjee;R. Levitch;Rakesh Kumar;Zhixin Wang;Christine Thorburn;Samopriyo Maitra;Shujie Li;Aurelie Verles;M. Dahlke;A. Risitano - 通讯作者:
A. Risitano
Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48 Weeks: 307 Open-Label Extension Study
Pegcetacoplan 在 48 周内治疗阵发性睡眠性血红蛋白尿成人患者的安全性和有效性:307 项开放标签扩展研究
- DOI:
10.1007/s12325-024-02827-8 - 发表时间:
2024 - 期刊:
- 影响因子:3.8
- 作者:
Christopher J. Patriquin;Andrija Bogdanovic;Morag Griffin;Richard J. Kelly;Jaroslaw P Maciejewski;Brian P Mulherin;Régis Peffault de Latour;Alexander Röth;Veena Selvaratnam;Jeff Szer;M. Al;R. Horneff;Lisa Tan;M. Yeh;Jens Panse - 通讯作者:
Jens Panse
Jaroslaw P Maciejewski的其他文献
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{{ truncateString('Jaroslaw P Maciejewski', 18)}}的其他基金
Therapeutic Implications of Molecular Defects in Bone Marrow Failure
骨髓衰竭中分子缺陷的治疗意义
- 批准号:
10629041 - 财政年份:2022
- 资助金额:
$ 60.83万 - 项目类别:
Therapeutic Implications of Molecular Defects in Bone Marrow Failure
骨髓衰竭中分子缺陷的治疗意义
- 批准号:
10323011 - 财政年份:2017
- 资助金额:
$ 60.83万 - 项目类别:
Therapeutic Implications of Molecular Defects in Bone Marrow Failure
骨髓衰竭中分子缺陷的治疗意义
- 批准号:
10762094 - 财政年份:2017
- 资助金额:
$ 60.83万 - 项目类别:
Therapeutic Implications of Molecular Defects in Bone Marrow Failure
骨髓衰竭中分子缺陷的治疗意义
- 批准号:
10080100 - 财政年份:2017
- 资助金额:
$ 60.83万 - 项目类别:
Therapeutic Implications of Molecular Defects in Bone Marrow Failure
骨髓衰竭中分子缺陷的治疗意义
- 批准号:
10545045 - 财政年份:2017
- 资助金额:
$ 60.83万 - 项目类别:
Novel Spliceosomal Defects in Myelodysplastic Syndromes
骨髓增生异常综合征中的新型剪接体缺陷
- 批准号:
9080763 - 财政年份:2016
- 资助金额:
$ 60.83万 - 项目类别:
The Role of Somatic Mutations in Aplastic Anemia
体细胞突变在再生障碍性贫血中的作用
- 批准号:
8942834 - 财政年份:2015
- 资助金额:
$ 60.83万 - 项目类别:
Investigations of Consequences of U2AF1 Mutations in MDS
MDS 中 U2AF1 突变后果的研究
- 批准号:
8666590 - 财政年份:2013
- 资助金额:
$ 60.83万 - 项目类别:
Investigations of Consequences of U2AF1 Mutations in MDS
MDS 中 U2AF1 突变后果的研究
- 批准号:
8482808 - 财政年份:2013
- 资助金额:
$ 60.83万 - 项目类别:
Investigations of Consequences of U2AF1 Mutations in MDS
MDS 中 U2AF1 突变后果的研究
- 批准号:
8828772 - 财政年份:2013
- 资助金额:
$ 60.83万 - 项目类别:
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