Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, a cognitive impairment syndrome. Histone acetylation is generally associated with active gene transcription. Genetic deletion of both alleles of the Kat6a gene in mice causes developmental defects including anterior homeotic transformation, cleft palate, interrupted aortic arch and cardiac septal defects. Loss of KAT6A impairs expression of HOX, DLX and TBX genes, which are essential for body segment identity specification, palate, heart and aortic arch development. However, the effects of loss of KAT6A on chromatin modifications and gene expression in neural cells, which are relevant to normal brain development and function, is still poorly understood. In this study, we used an automated high-throughput chromatin profiling method and RNA sequencing in mouse neural system and progenitor cells to assess the effects of loss of one or two alleles of Kat6a on gene expression, histone acetylation and methylation. We also assessed occupancy by a trithorax group protein and RNA polymerase II. Our data suggests two modes of action for KAT6A: (1) acetylation of histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of the trithorax group protein MLL1 (KMT2A) to promote the expression of developmental genes, including SOX and homeodomain genes. Together, these two functions appear to be required for normal gene expression in neural progenitors and essential for proliferation and neuronal differentiation. Author summaryDuring embryonic development, specific families of transcription factors pattern the early embryo to lay down and define the body and organ structure. However, the mechanisms governing the onset of the expression of these developmental transcription factors in less well understood. KAT6A is thought to promote gene expression by acetylation histone proteins. Here we determine the effects of KAT6A on histone acetylation and gene expression in mouse neural stem and progenitor cells. Our data are relevant for the understanding of pathogenic genetic variants in one allele of the human KAT6A gene, which cause the Arboleda-Tham cognitive impairment syndrome.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response.

IntroductionDiffuse midline glioma (DMG) with the H3K27M mutation remains one of the most treatment-resistant pediatric brain tumors, in part due to limited antigen presentation and immune visibility. Exploring how glioma biology and therapeutic interventions influence immune recognition offers new opportunities to identify tumor-specific immune targets.Materials and MethodsWe performed immunopeptidomics on human cell line derived tumor tissue for DMG and glioblastoma (GBM) and defined how MTX-241F, a selective EGFR/PI3K inhibitor, changes the tumor immunopeptidome. Immunopeptides were isolated from xenografted tumors by capturing MHC-I bound peptides followed by mass spectrometry. Comparative analyses were performed across tumor type (DMG vs. GBM) and treatment condition (vehicle vs. MTX-241F).ResultsImmunopeptidomic profiling revealed tumor-specific differences in peptide repertoires between DMG and GBM. GBM tumors exhibited twice as many immunopeptides as DMG, which may be due to the distinct biology of each tumor type or may be indicative of potential HLA allotype composition. We identified highly abundant H2B1K-derived immunopeptides in DMG, suggesting that the H3K27M-driven epitranscriptome may promote turnover of other histones. MTX-241F increased the number of immunopeptides in DMG but reduced them in GBM, indicating a tumor-specific change in the immunopeptidome following EGFR/PI3K inhibition. In addition, we identified brain-enriched, HLA-A*02:01–binding and MTX-241F–exclusive immunopeptides that represent treatment-induced changes and may serve as biomarkers of therapeutic response or potential targets for CAR-T cell-based approaches.DiscussionMTX-241F changes the glioma immunopeptidome, unveiling H2B1K, brain-enriched, and treatment-induced immunopeptides as immunologically visible targets. These findings provide a rationale for integrating molecularly targeted therapy with immunotherapeutic approaches to enhance tumor recognition and treatment efficacy in DMG and GBM.