The role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade glioma
ATRX 突变在儿童高级别胶质瘤细胞周期表观遗传失调中的作用
基本信息
- 批准号:10641820
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATRX geneAutomobile DrivingBindingBrainBrain StemCHEK1 geneCHEK2 geneCell CycleCell Cycle CheckpointCell Cycle ProgressionCell Cycle RegulationCellsChildhoodChildhood GliomaDNADNA DamageDNA RepairDNA replication forkDataDependenceDepositionDevelopmentDiffuse intrinsic pontine gliomaEnhancersEpigenetic ProcessFunctional disorderGeneticGenetically Engineered MouseGliomaH3 K27M mutationHistone H3HistonesHumanImpairmentKnowledgeMaintenanceMalignant Childhood NeoplasmModelingMusMutateMutationNormal CellOutcomePathway interactionsPatientsPhasePhenotypePre-Clinical ModelProteinsPsychological reinforcementRadiation ToleranceRadiation therapyRadiosensitizationRegulator GenesResearchRoleScienceSiteSubgroupSurvival RateTissuesTranscriptional RegulationTranslatingUntranslated RNAVariantchromatin remodelingcomparison controlembryonic stem cellexperimental studygain of function mutationgenomic locusinhibitorirradiationknock-downloss of function mutationmouse modelmutantnew therapeutic targetnoveloverexpressionpermissivenesspharmacologicprecursor cellpromotertargeted treatment
项目摘要
PROJECT SUMMARY / ABSTRACT
Background and long-term objectives: Pediatric high-grade glioma (pHGG) is among the most lethal pediatric
cancers, and new targeted therapies are desperately needed. Approved therapies for pHGG remain non-
targeted and 2-year survival rates are less than 20%. Loss of function mutations in the chromatin remodeling
protein ATRX are found in 30% of pHGG and DIPG, usually with concurrent mutation in the histone variant
H3F3A (H3.3). We previously developed a mouse model of ATRX-deficient GBM and showed that loss of ATRX
results in increased sensitivity to radiation treatment. We recently discovered that HGG cells with isogenic ATRX
loss demonstrate inappropriate release of G1/S and G2/M checkpoint after irradiation and radio-sensitization
with inhibitors of the master cell cycle regulator ATM. However, the mechanism driving this phenotype has not
been established, and no models utilizing a background of pHGG mutations (e.g. H3.3) have been employed to
study ATRX loss. Thus, there is a critical need to determine how ATRX loss deregulates cell cycle checkpoints,
and to clarify the impact of concurrent H3F3A mutation on cell cycle regulation and radiation sensitizing therapy.
In the absence of such knowledge, the ability to translate therapies targeted to the cell cycle checkpoint deficit
in ATRX-deficient pHGG will remain unlikely.
Our overall objective in this proposal is to determine the epigenetic mechanism of cell cycle dysfunction in ATRX
mutated-pHGG and the impact/targetability of concurrent H3F3A mutation. Our central hypothesis is that ATRX
mutation in pHGG results in reduced H3.3-promotor binding and expression of the cell cycle checkpoint regulator
Checkpoint Kinase 1 (CHK1), leading to permissive cell cycle checkpoints after DNA damage. We propose that
co-occurrence of H3K27M mutation will enhance this deficit and increase radio-sensitization with ATM inhibition.
This is based on our preliminary data demonstrating (i) ATRX/H3.3 deposition at CHEK1 promoter sites, (ii)
reduction in Chk1 expression and checkpoint maintenance after irradiation in ATRX deficient models, and (iii)
increased cell cycle release with ATM inhibition in H3K27M cells compared to controls.
Specific Aim 1: Determine the mechanism of cell-cycle phase dysfunction in ATRX-deficient pHGG. We
will accomplish this by integrating complementary experimental approaches of multiple human and mouse pre-
clinical models of ATRX loss in pHGG, including epigenetic, cell cycle and DNA-damage repair experiments.
Specific Aim 2: Determine the impact of co-occurring H3F3A mutation on the targetability of ATRX-
deficient pHGG. We will accomplish this Aim by integrating multiple human and mouse pre-clinical models of
ATRX loss in pHGG, including a novel genetically engineered mouse model with isogenic control of H3F3A
and ATRX, to isolate contribution of each driver on cell-cycle deficit and targetability.
Our integrative experimental approach will establish the mechanism behind the phenotypes we have recently
discovered and open new windows for therapies targeted to the unique features of ATRX-deficient pHGG.
项目总结/摘要
背景和长期目标:小儿高级别胶质瘤(pHGG)是最致命的小儿胶质瘤之一,
癌症和新的靶向治疗是迫切需要的。批准的pHGG治疗仍然没有
目标和2年生存率低于20%。染色质重塑中的功能缺失突变
在30%的pHGG和DIPG中发现蛋白ATRX,通常在组蛋白变体中同时发生突变
H3F3A(H3.3)。我们以前开发了一种ATRX缺陷GBM的小鼠模型,并表明ATRX的缺失
导致对放射治疗的敏感性增加。我们最近发现具有同基因ATRX的HGG细胞
丢失表明照射和放射增敏后G1/S和G2/M检查点的不适当释放
与主细胞周期调节剂ATM的抑制剂。然而,驱动这种表型的机制还没有
已经建立,并且没有利用pHGG突变背景(例如H3.3)的模型被用于
研究ATRX损失。因此,迫切需要确定ATRX损失如何去调节细胞周期检查点,
并阐明H3 F3 A突变对细胞周期调控和放射增敏治疗的影响。
在缺乏这些知识的情况下,将靶向细胞周期检查点缺陷的疗法转化为治疗的能力
在ATRX缺陷型pHGG中仍然不太可能。
我们的总体目标是确定ATRX中细胞周期功能障碍的表观遗传机制
突变的pHGG和并发H3 F3 A突变的影响/靶向性。我们的中心假设是ATRX
pHGG突变导致H3.3启动子结合和细胞周期检查点调节因子表达减少
检查点激酶1(CHK 1),导致DNA损伤后允许的细胞周期检查点。我们建议
H3 K27 M突变的共同出现将增强这种缺陷,并增加ATM抑制的放射增敏作用。
这是基于我们的初步数据,表明(i)ATRX/H3.3沉积在CHEK 1启动子位点,(ii)
在ATRX缺陷模型中照射后Chk 1表达和检查点维持减少,和(iii)
与对照相比,在H3 K27 M细胞中ATM抑制增加细胞周期释放。
具体目的1:确定ATRX缺陷型pHGG细胞周期时相功能障碍的机制。我们
将通过整合多种人类和小鼠预处理的互补实验方法来实现这一目标。
pHGG中ATRX损失的临床模型,包括表观遗传、细胞周期和DNA损伤修复实验。
具体目的2:确定共发生的H3 F3 A突变对ATRX靶向性的影响-
pHGG缺陷。我们将通过整合多种人类和小鼠临床前模型来实现这一目标。
pHGG中的ATRX损失,包括具有H3 F3 A的同基因控制的新型基因工程小鼠模型
和ATRX,以分离每种驱动因子对细胞周期缺陷和靶向性的贡献。
我们的综合实验方法将建立我们最近发现的表型背后的机制。
发现并为靶向ATRX缺陷型pHGG的独特特征的疗法打开了新的窗口。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid.
- DOI:10.1016/j.xcrm.2023.101148
- 发表时间:2023-08-15
- 期刊:
- 影响因子:14.3
- 作者:Douville, Christopher;Curtis, Samuel;Summers, Mahmoud;Azad, Tej D.;Rincon-Torroella, Jordina;Wang, Yuxuan;Mattox, Austin;Avigdor, Bracha;Dudley, Jonathan;Materi, Joshua;Raj, Divyaansh;Nair, Sumil;Bhanja, Debarati;Tuohy, Kyle;Dobbyn, Lisa;Popoli, Maria;Ptak, Janine;Nehme, Nadine;Silliman, Natalie;Blair, Cherie;Judge, Kathy;Gallia, Gary L.;Groves, Mari;Jackson, Christopher M.;Jackson, Eric M.;Laterra, John;Lim, Michael;Mukherjee, Debraj;Weingart, Jon;Naidoo, Jarushka;Koschmann, Carl;Smith, Natalya;Schreck, Karisa C.;Pardo, Carlos A.;Glantz, Michael;Holdhoff, Matthias;Kinzler, Kenneth W.;Papadopoulos, Nickolas;Vogelstein, Bert;Bettegowda, Chetan
- 通讯作者:Bettegowda, Chetan
TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory.
- DOI:10.1016/j.ccell.2023.09.001
- 发表时间:2023-11-13
- 期刊:
- 影响因子:50.3
- 作者:Ausejo-Mauleon, Iker;Labiano, Sara;de la Nava, Daniel;Laspidea, Virginia;Zalacain, Marta;Marrodan, Lucia;Garcia-Moure, Marc;Gonzalez-Huarriz, Marisol;Hervas-Corpion, Irati;Dhandapani, Laasya;Vicent, Silvestre;Collantes, Maria;Penuelas, Ivan;Becher, Oren J.;Filbin, Mariella G.;Jiang, Li;Labelle, Jenna;de Biagi-Junior, Carlos A. O.;Nazarian, Javad;Laternser, Sandra;Phoenix, Timothy N.;van der Lugt, Jasper;Kranendonk, Mariette;Hoogendijk, Raoull;Mueller, Sabine;De Andrea, Carlos;Anderson, Ana C.;Guruceaga, Elizabeth;Koschmann, Carl;Yadav, Viveka Nand;Perez-Larraya, Jaime Gallego;Patino-Garcia, Ana;Pastor, Fernando;Alonso, Marta M.
- 通讯作者:Alonso, Marta M.
OpenPBTA: The Open Pediatric Brain Tumor Atlas.
- DOI:10.1016/j.xgen.2023.100340
- 发表时间:2023-07-12
- 期刊:
- 影响因子:0
- 作者:Shapiro, Joshua A.;Gaonkar, Krutika S.;Spielman, Stephanie J.;Savonen, Candace L.;Bethell, Chante J.;Jin, Run;Rathi, Komal S.;Zhu, Yuankun;Egolf, Laura E.;Farrow, Bailey K.;Miller, Daniel P.;Yang, Yang;Koganti, Tejaswi;Noureen, Nighat;Koptyra, Mateusz P.;Duong, Nhat;Santi, Mariarita;Kim, Jung;Robins, Shannon;Storm, Phillip B.;Mack, Stephen C.;Lilly, Jena, V;Xie, Hongbo M.;Jain, Payal;Raman, Pichai;Rood, Brian R.;Lulla, Rishi R.;Nazarian, Javad;Kraya, Adam A.;Vaksman, Zalman;Heath, Allison P.;Kline, Cassie;Scolaro, Laura;Viaene, Angela N.;Huang, Xiaoyan;Way, Gregory P.;Foltz, Steven M.;Zhang, Bo;Poetsch, Anna R.;Mueller, Sabine;Ennis, Brian M.;Prados, Michael;Diskin, Sharon J.;Zheng, Siyuan;Guo, Yiran;Kannan, Shrivats;Waanders, Angela J.;Margol, Ashley S.;Kim, Meen Chul;Hanson, Derek;Van Kuren, Nicholas;Wong, Jessica;Kaufman, Rebecca S.;Coleman, Noel;Blackden, Christopher;Cole, Kristina A.;Mason, Jennifer L.;Madsen, Peter J.;Koschmann, Carl J.;Stewart, Douglas R.;Wafula, Eric;Brown, Miguel A.;Resnick, Adam C.;Greene, Casey S.;Rokita, Jo Lynne;Taroni, Jaclyn N.
- 通讯作者:Taroni, Jaclyn N.
{{
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 }}
Carl J Koschmann其他文献
Carl J Koschmann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('Carl J Koschmann', 18)}}的其他基金
Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma
在 H3K27M 突变的弥漫性中线神经胶质瘤中靶向 EGFR/FOXG1 介导的 ONC201 耐药性
- 批准号:
10556344 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma
在 H3K27M 突变的弥漫性中线神经胶质瘤中靶向 EGFR/FOXG1 介导的 ONC201 耐药性
- 批准号:
10337525 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
The role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade glioma
ATRX 突变在儿童高级别胶质瘤细胞周期表观遗传失调中的作用
- 批准号:
10432082 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
The role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade glioma
ATRX 突变在儿童高级别胶质瘤细胞周期表观遗传失调中的作用
- 批准号:
10294010 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)