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: 10641820
• 负责人: Carl J Koschmann
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10641820
• 关键词: ATRX gene; Automobile Driving; Binding; Brain; Brain Stem; CHEK1 gene; CHEK2 gene; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cells; Childhood; Childhood Glioma; DNA; DNA Damage; DNA Repair; DNA replication fork; Data; Dependence; Deposition; Development; Diffuse intrinsic pontine glioma; Enhancers; Epigenetic Process; Functional disorder; Genetic; Genetically Engineered Mouse; Glioma; H3 K27M mutation; Histone H3; Histones; Human; Impairment; Knowledge; Maintenance; Malignant Childhood Neoplasm; Modeling; Mus; Mutate; Mutation; Normal Cell; Outcome; Pathway interactions; Patients; Phase; Phenotype; Pre-Clinical Model; Proteins; Psychological reinforcement; Radiation Tolerance; Radiation therapy; Radiosensitization; Regulator Genes; Research; Role; Science; Site; Subgroup; Survival Rate; Tissues; Transcriptional Regulation; Translating; Untranslated RNA; Variant; chromatin remodeling; comparison control; embryonic stem cell; experimental study; gain of function mutation; genomic locus; inhibitor; irradiation; knock-down; loss of function mutation; mouse model; mutant; new therapeutic target; novel; overexpression; permissiveness; pharmacologic; precursor cell; promoter; targeted treatment

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.

项目摘要/摘要

项目成果

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: CELL REPORTS MEDICINE
• 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: CANCER CELL
• 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: CELL GENOMICS
• 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.