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Diffuse midline gliomas (DMG) have a generally poor prognosis and limited treatment options. DMGs are driven by amino acid substitutions in genes encoding for H3K27M oncohistones, which lead to altered chromatin architecture and aberrant epigenetic landscapes. Two studies by Panditharatna, Marques, and colleagues (page 2880) and Mo, Duan, Zhang, and colleagues (page 2906) sought to determine the molecular mechanisms that underlie the epigenetic dependencies of DMG and showed that SMARCA4, the ATPase subunit of the BAF complex, is critical for DMG tumorigenesis and that targeting SMARCA4 could provide potential therapeutic benefit to patients. Panditharatna, Marques, and colleagues demonstrated that both enhancer and transcription factor states are regulated by components of the BAF complex and that SMARCA4 perturbation, either genetically or pharmacologically, reduces proliferation and improves overall survival in patient-derived xenograft mouse models. Mo, Duan, Zhang, and colleagues found that SMARCA4 inhibition reduced fitness of DMG cells as well as the growth of DMG xenografts and that SMARCA4 recruitment to gene regulatory elements of genes necessary for cell growth or extracellular matrix is mediated by the transcription factor SOX10. For more information, see the corresponding articles at the page numbers listed above. - PDF Icon PDF LinkTable of Contents
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Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis
This subgroup analysis of patients with HER2-positive breast cancer with a history of brain metastases from DESTINY-Breast01 demonstrated the strong clinical activity of trastuzumab deruxtecan (T-DXd) in this patient population, warranting continued investigation.
Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis
In DNMT3A-mutant clonal hematopoiesis, the selective advantage of mutant hematopoietic stem cells is potentiated by TNFα–TNFR1 signaling, whereas TNFα–TNFR2 signaling specifies the lineage(s) of mature mutant blood cell types produced.
Research Articles
Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade
Remodeling of pancreatic ductal adenocarcinoma tumor–stroma interactions by FAK inhibition allows radiation therapy to prime antitumor immunity and unlock responsiveness to immunotherapy.
Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma
Serial circulating tumor DNA profiling in patients with neuroblastoma identifies dynamic tumor evolution, disease progression, and functionally relevant variants beyond that of standard clinical surveillance and direct tumor sequencing practices.
Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma
Single-cell transcriptomics of multifocal glioblastomas characterized properties of natural tumor evolution, as well as tumor migration and immunoenvironment remodeling.
Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture
Integrative 3D genomic analysis reveals that many germline risk alleles and somatic driver mutations dysregulate transcription in prostate cancer via enhancer reprogramming and long-range chromatin interactions.
Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Cutaneous, acral, and mucosal melanomas have alterations in components of MAPK, PI3K, p53, p16, and telomere pathways but different mechanisms of activation or inactivation, whereas uveal melanomas are genomically distinct.
BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma
The BAF complex, in particular ATPase subunit SMARCA4/BRG1, is critical for maintaining pediatric H3K27M-glioma cells in an oncogenic progenitor state, and pharmacologic inhibition is a potential therapeutic avenue for these highly aggressive tumors.
Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4
SMARCA4, the catalytic subunit of mammalian SWI/SNF complex, is critical for H3K27-Maltered diffuse midline glioma cells as well as regulates their gene expression and fitness, which suggests SMARCA4 as a potential therapeutic approach for this lethal disease.
Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
In vivo CRISPR screening identified loss of epigenetic regulation as a critical tumorsuppressive mechanism that leads to basal mammary epithelial cell lineage infidelity, aberrant alveolar differentiation, and the acceleration of luminal breast tumor initiation.
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