Mechanisms and Modeling of Neuroblastoma-Associated ATRX Alterations

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Principal Investigator: Emily  Bernstein
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $388,937
Funding agency: National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY
Epigenetic deregulation is now widely accepted as a hallmark of pediatric cancer. Mutations and structural
alterations of the SWI/SNF-like chromatin remodeler ATRX (Alpha Thalassemia/Mental Retardation, X-
linked) have been reported at high frequency in a number of adult and pediatric tumors. However, the
consequences of ATRX mutations in cancer and their underlying epigenetic sensitivities remain ill defined.
Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma (NB) found in older
children and adolescents that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction
modules. Our preliminary data suggests that NB cells harboring ATRX IFFs have distinct gene expression
programs compared to WT ATRX NB cells. This is due in part to H3K27me3-mediated silencing of REST
(RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that
ATRX IFF cells display sensitivity to EZH2 inhibition (EZH2i) in vitro and in vivo. However, the role of ATRX
IFFs in indolent NB remains poorly understood. In order to decipher the underlying mechanisms of
neuronal gene silencing in ATRX IFF NB, and how to alleviate it and induce cell death, we will determine
the role of ATRX IFF proteins in promoting NB development through functional, epigenomic and proteomic
studies (AIM 1), and define NB transcriptomes and EZH2/H3K27me3/REST target genes in NB cells +/-
EZH2i (AIM 2). These integrated epigenomic, proteomic and transcriptional studies will reveal the
consequences of ATRX structural alterations in NB in development and provide rationale for EZH2
inhibition as a strategy to treat ATRX-altered NB.
 
 

Terms: <0-11 years old><21+ years old><ATPase Domain><ATRX><ATRX gene><Adolescent><Adolescent Youth><Adult><Adult Human><Antimorphic mutation><Automobile Driving><Binding><Bone Sarcoma><C-terminal><Cancers><Cell Body><Cell Death><Cell Death Induction><Cell Line><Cell fusion><CellLine><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Characteristics><Child><Child Youth><Childhood Cancers><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Chimera Protein><Chimeric Proteins><Chromatin><Clinical><Cloning><Collaborations><Complex><DIPG><DNA Helicases><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA Unwinding Proteins><DNA unwinding enzyme><DNA-Methyltransferases><Data><Development><Diffuse intrinsic pontine glioma><Disease><Disorder><Dnmt><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Drug Therapy><ENX-1><EZH1><EZH2><EZH2 gene><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Experimental Models><Frequencies><Fusion Protein><Gene Expression><Gene Inactivation><Gene Silencing><Gene Targeting><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Genomics><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Heterograft><Heterologous Transplantation><Histone H3><In Vitro><Indolent><KMT6><KMT6A><L-Lysine><Length><Lysine><MSKCC><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Mediating><Memorial Sloan-Kettering Cancer Center><Modeling><Modification Methylases><Molecular Interaction><Mutation><N-terminal><NH2-terminal><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neural Stem Cell><Neuroblastoma><Neurocyte><Neuroglial Neoplasm><Neuroglial Tumor><Neurologic Body System><Neurologic Organ System><Neuronal Differentiation><Neurons><Oncogenic><Osseous Sarcoma><Osteogenic Sarcoma><Osteosarcoma><PDX model><Patient derived xenograft><Patients><Pediatric Neoplasm><Pediatric Tumor><Pharmacotherapy><Phenotype><Point Mutation><Proliferating><Proteins><Proteomics><RE1-silencing transcription factor><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Recurrence><Recurrent><Reporting><Role><Site-Specific DNA-methyltransferase><Skeletal Sarcoma><Strains Cell Lines><Therapeutic><Transcription><X-linked a-thalassemia mental retardation><X-linked alpha thalassemia retardation><X-linked alpha-thalassemia mental retardation><X-linked alpha-thalassemia/mental retardation syndrome><X-linked α-thalassemia retardation><X-linked α-thalassemia/mental retardation syndrome><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><adulthood><alpha thalassemia mental retardation X-linked gene><cancer in a child><cancer in children><cartilage link protein><child with cancer><childhood malignancy><chromatin immunoprecipitation-sequencing><clinical subtypes><cultured cell line><derepression><developmental><disease phenotype><driving><drug treatment><effective therapy><effective treatment><epigenetically><epigenome><epigenomics><genome mutation><glial-derived tumor><global gene expression><global transcription profile><helicase><histone methylation><in vivo><in vivo Model><inhibitor><innovate><innovation><innovative><juvenile><juvenile human><kids><knock-down><knockdown><link protein><malignancy><migration><necrocytosis><neoplasm/cancer><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuroblastoma cell><neuroglia neoplasm><neuroglia tumor><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><nondeletion type alpha-thalassemia/mental retardation syndrome><novel><osteochondrosarcoma><osteoid sarcoma><overexpress><overexpression><patient derived xenograft model><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pediatric cancer><pediatric department><pediatric malignancy><programs><response><shRNA><short hairpin RNA><small hairpin RNA><social role><therapeutic target><transcriptional silencing><transcriptome><transcriptome sequencing><transcriptomic sequencing><tumor><tumors in children><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model><youngster><α-thalassemia mental retardation X-linked gene>