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Статті в журналах з теми "Oncohistone H3.3 K27M":
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Liu, Ilon, Jiang Li, Daeun Jeong, Olivia A. Hack, McKenzie Shaw, Bernhard Englinger, Byron Avihai, et al. "EPCO-06. AGE- AND REGION-SPECIFIC MULTI-OMIC CHARACTERIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi2. http://dx.doi.org/10.1093/neuonc/noab196.005.
Анотація:
Abstract Diffuse midline gliomas driven by lysine27-to-methionine mutations in histone 3 (H3-K27M DMGs) are among the most fatal brain tumors. Molecular studies including single cell RNA-sequencing (scRNA-seq) of pediatric and predominantly pontine H3-K27M DMGs have shown that the H3-K27M oncohistone keeps glioma cells locked in a stem-like oligodendrocyte precursor cell (OPC) state that is capable of self-renewal and tumor-initiation. However, a comprehensive dissection of the cellular architecture of H3-K27M DMGs across different midline regions and age groups is required to better understand the cell-intrinsic and contextual regulation of H3-K27M DMG cell identities. In particular, the more recently described group of adult H3-K27M DMGs remains understudied. Here, we have collected and characterized 45 H3-K27M mutant patient tumors, spanning pontine (n=26), thalamic (n=17), and spinal (n=2) locations. Median age at surgery was 12 (2-68) years, encompassing 21 early childhood (0-10 years), 12 adolescent (11-20 years), and 12 adult (≥ 21 years) tumors. The majority of samples were obtained pre-treatment (n=28), as opposed to post-treatment or at autopsy (n=17). We profiled all 45 tumors by single cell/single nucleus RNA-seq and selected tumors were further characterized by the single cell assay for transposase-accessible chromatin (scATAC-seq). Our integrated analyses highlight the predominance of transcriptionally and epigenetically defined OPC-like tumor cells as the main cell population of H3-K27M DMGs across all age groups and locations. We further identify distinct age- and location-specific OPC-like cell subpopulations. Comparison of pediatric and adult tumors further demonstrates a significant increase of mesenchymal cell states in adult H3-K27M DMGs, which we link to differences in glioma-associated immune cell compartments between age groups. Together, this study sheds light on the effects of age- and region-dependent microenvironments in shaping cellular identities in H3-K27M DMGs.
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Liu, I., L. Jiang, E. Samuelsson, S. Marco Salas, O. Hack, D. Jeong, M. Shaw, et al. "JS04.6.A The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii7. http://dx.doi.org/10.1093/neuonc/noac174.021.
Анотація:
Abstract Background Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied. Material and Methods Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. Results We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments. We for the first time resolve the spatial organization of H3-K27M DMG cell types in intact patient tissues, identifying a local niche of the oligodendroglial lineage. Conclusion Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
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Liu, Ilon, Li Jiang, Erik Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia Hack, Daeun Jeong, et al. "DIPG-08. THE LANDSCAPE OF TUMOR CELL STATES AND SPATIAL ORGANIZATION IN H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA ACROSS AGE AND LOCATION." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i14. http://dx.doi.org/10.1093/neuonc/noad073.055.
Анотація:
Abstract Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus, and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied. Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments, in particular an increase of macrophages in adult compared to pediatric tumors. Furthermore, we resolve the spatial organization of H3-K27M DMG cell types and states in intact patient tissues, identifying a local niche of the oligodendroglial lineage. Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
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Hübner, Jens-Martin, Torsten Müller, Dimitris N. Papageorgiou, Monika Mauermann, Jeroen Krijgsveld, Robert B. Russell, David W. Ellison, Stefan M. Pfister, Kristian W. Pajtler, and Marcel Kool. "EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma." Neuro-Oncology 21, no. 7 (April 29, 2019): 878–89. http://dx.doi.org/10.1093/neuonc/noz058.
Анотація:
Abstract Background Posterior fossa A (PFA) ependymomas are one of 9 molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of chromosome X open reading frame 67 (CXorf67) as a hallmark of PFA ependymoma and showed that CXorf67 can interact with enhancer of zeste homolog 2 (EZH2), thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear. Methods We performed mass spectrometry and peptide modeling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot, and methyltransferase assays. Results We find that the inhibitory mechanism of CXorf67 is similar to diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain (Su(var)3-9/enhancer-of-zeste/trithorax) of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function, causing de-repression of PRC2 target genes, including genes involved in neurodevelopment. Conclusions Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 as “EZH Inhibitory Protein” (EZHIP).
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Liapodimitri, Athanasia, Kayleigh Lunsford, Ashley R. Tetens, Jordyn Craig-Schwartz, Farhad Vesuna, Venu Raman, and Michael A. Koldobskiy. "DIPG-64. UNRAVELING H3K27M INTERACTIONS IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.117.
Анотація:
Abstract BACKGROUND Diffuse midline glioma (DMG) harboring the histone H3 K27M mutation, also known as diffuse intrinsic pontine glioma when it occurs in the pons, is a uniformly fatal pediatric brain tumor. We sought to better understand protein-protein interactions of the mutant histone in DMG. METHODS To address this, we carried out endogenous co-immunoprecipitation of histone H3 K27M from patient-derived DMG neurosphere cell lines, followed by LC-MS/MS identification of binding partners, and validation of binding by Western Blot. Moving beyond identification, we investigated the functional consequences of these interactions. RESULTS We identified putative novel interactors of H3 K27M with notable binding partners including histone chaperones and RNA helicases of the DDX family. We then explored the disruption of downstream effects resulting from this interaction by pharmacologically inhibiting DDX3 using the small molecule inhibitor RK-33, and assessed impact on viability and radiation sensitivity. CONCLUSIONS Understanding the protein interactome of the mutant histone can inform alternative ways for targeting DMG, thus enriching the therapeutic toolbox against this aggressive tumor. Functional characterization of binding partners holds the potential to identify novel therapeutic targets that cooperate with H3 K27M. The use of inhibitors targeting these partners could specifically destabilize oncohistone-dependent homeostasis and survival pathways and increase sensitivity to radiation and other therapies.
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Andrade, Augusto Faria, Danai Topouza, Michael McNicholas, Eduardo G. Gonzalez Santiago, Antonella De Cola, Arne Gehlhaar, Selin Jessa, et al. "TMIC-04. IMMUNE PROFILING OF PEDIATRIC ONCOHISTONE GLIOMAS REVEALS DIVERSE MYELOID POPULATIONS AND TUMOR-PROMOTING BEHAVIORS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v278. http://dx.doi.org/10.1093/neuonc/noad179.1070.
Анотація:
Abstract Pediatric high-grade gliomas pHGG are lethal and frequently bear missense mutations in histone H3, which drive tumorigenesis by altering the epigenome and cell fate/differentiation. While previous studies showed intrinsic contingencies associated with tumor development, limited information exists on the tumor microenvironment (TME) and immune cells for these tumors. To define the immune landscape of pediatric tumors at single-cell resolution, we profiled and compared 69 pediatric gliomas samples using the Chromium 10X technologies, H3.3 K27M (N=19) and G34R (N=16) mutant tumors, low-grade gliomas (N=11) and ependymomas (N=23). Additionally, to enable the spatial resolution of immune lineages, we performed Imaging Mass Cytometry (IMC) on H3-mutant samples (H3.3 K27M (N=7) and G34R (N=5)). We demonstrate that pediatric histone H3-mutant gliomas are highly infiltrated by myeloid cells, more specifically resident microglia, bone-marrow derived macrophages (BMDM) and monocytes, and are devoid of lymphoid infiltration. Different myeloid subsets were found to interact with H3-mutant cancer cells. Classical BMDM showed strong interactions with H3-mutant cancer cells while monocytes subsets showed tendency to interact only with G34R cells. We have generated a novel H3.3K27M glioma immunocompetent murine model, establishing a highly-penetrant and reliable tool. H3.3K27M murine tumors recapitulated the TME from human tumors, showing great myeloid infiltration. Using in vivo orthotopic serial engraftments, we observed that secondaries transplanted tumors had a significantly worse survival, possessing a less diverse immune infiltration compared to initial engraftments and a dominant presence of myeloid cells. Interestingly, in vivo myeloid depletion combined with PD-1 blockade extended overall mice survival. Our findings provide a valuable characterization of the biology of these tumors, reinforcing the several roles of myeloid cells in the context of pediatric brain tumours, providing a framework for understanding the H3.3K27M and G34R tumors, including other pediatric gliomas, and designing future immunotherapies.
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Budd, Kaitlin, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, and Suzanne J. Baker. "Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): IA007. http://dx.doi.org/10.1158/1538-7445.cancepi22-ia007.
Анотація:
Abstract Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis. Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.
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Kida, Jun-ichiro, Takayuki Tsujioka, Shin-ichiro Suemori, Shuichiro Okamoto, Kanae Sakakibara, Takahiro Yamauchi, Akira Kitanaka, Yumi Tohyama, and Kaoru Tohyama. "Malignant Progression of an MDS-Derived Cell Line Serves As an in Vitro Model for the Leukemic Evolution of MDS." Blood 132, Supplement 1 (November 29, 2018): 5501. http://dx.doi.org/10.1182/blood-2018-99-110583.
Анотація:
Abstract Myelodysplastic syndromes (MDS) have a risk of progression to acute myeloid leukemia (AML), but the deterioration mechanisms of MDS and the alteration points still remain to be elucidated. We previously established a myelodysplastic cell line, MDS92 from the bone marrow of an MDS patient, and after a long-term interleukin(IL)-3-containing culture of MDS92, five blastic sublines including MDS-L were isolated. From MDS-L, we obtained two sublines, MDS-L-2007 and MDS-LGF after culture in the presence and absence of IL-3, respectively. To investigate the mechanism of leukemic evolution, we applied a next-generation sequencing (NGS) to the series of cell lines for comprehensive, comparative exome analyses, and searched for the origin of mutations by ultra-deep target sequencing of the original patient bone marrow. Whole exome sequencing and ultra-deep target sequencing demonstrated: (1) TP53 mutation was found in the patient bone marrow and this mutation was inherited by all subsequent cell lines; (2) CEBPA mutation was originally present in a small fraction of the bone marrow; (3) NRAS mutation emerged by chance during IL-3-containing culture; (4) HIST1H3C(K27M) mutation (Histone-H3-K27M) was newly detected at the generation of MDS-L from MDS92. H3-K27M mutation was detected in MDS-L-2007 but not in MDS-LGF. We focused on H3-K27M mutation because it is frequently found in pediatric brain stem tumors and recently found in a small population of AML cases (Lehnertz et al. Blood. 2017). MDS-L cells were a mixture of H3-K27M-mutant and wild-type clones. When MDS-L was cultured in the presence of IL-3, the proportion of H3-K27M-mutant fraction gradually increased. In contrast, when MDS-L was cultured without IL-3, the proportion of H3-K27M-mutant fraction gradually decreased. To investigate the implication of H3-K27M mutation, we tried single cell cloning from MDS-L and secured four wild-type clones and seven H3-K27M-mutant clones. In all H3-K27M-mutant clones, there was a marked reduction in H3-K27me3/2. Expression of a tumor-suppressor molecule p16 was reduced in six of the seven H3-K27M-mutant clones. H3-K27M-mutant clones showed rapid growth in the presence of IL-3, but cell proliferation was suppressed without IL-3. Competitive growth experiment by co-culture of H3-K27-wild-type and H3-K27M-mutant clones in the presence or absence of IL-3 showed that H3-K27M-mutant clones were predominant in the presence of IL-3, whereas wild-type clones were sustained comparatively in the absence of IL-3. Treatment with EPZ-6438, an inhibitor of H3-K27 methyltransferase EZH2, caused growth suppression of H3-K27M-mutant clones as well as wild-type clones and involved obvious recovery of p16 expression in H3-K27M-mutant clones, which provides a possibility that p16 might be a therapeutic target for H3-K27M mutant. Although GSK-J4, an inhibitor of H3-K27 demethylase JMJD3, was reported to inhibit H3-K27M-mutated pediatric brain stem tumors, GSK-J4 exerted only non-specific growth inhibitory effect on both H3-K27M-mutant and wild-type clones. Whole exome analyses indicated that the accumulation of oncogenic mutations seemed to have led to establishment of MDS cell lines. The finding that growth advantage of H3-K27M mutant was influenced by the presence or absence of IL-3 raised a possibility that even if neoplastic clones emerge, their expansion might be influenced not only by genetic/epigenetic status but by surrounding environmental factors including cytokines. This series of cell lines will be a useful tool as an in vitro model for leukemic evolution of MDS. Disclosures No relevant conflicts of interest to declare.
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Hohm, Annika, Michael Karremann, Gerrit H. Gielen, Torsten Pietsch, Monika Warmuth-Metz, Lindsey A. Vandergrift, Brigitte Bison, et al. "Magnetic Resonance Imaging Characteristics of Molecular Subgroups in Pediatric H3 K27M Mutant Diffuse Midline Glioma." Clinical Neuroradiology 32, no. 1 (December 17, 2021): 249–58. http://dx.doi.org/10.1007/s00062-021-01120-3.
Анотація:
Abstract Purpose Recent research identified histone H3 K27M mutations to be associated with a dismal prognosis in pediatric diffuse midline glioma (pDMG); however, data on detailed MRI characteristics with respect to H3 K27 mutation status and molecular subgroups (H3.1 and H3.3 K27M mutations) are limited. Methods Standardized magnetic resonance imaging (MRI) parameters and epidemiologic data of 68 pDMG patients (age <18 years) were retrospectively reviewed and compared in a) H3 K27M mutant versus H3 K27 wildtype (WT) tumors and b) H3.1 versus H3.3 K27M mutant tumors. Results Intracranial gliomas (n = 58) showed heterogeneous phenotypes with isointense to hyperintense signal in T2-weighted images and frequent contrast enhancement. Hemorrhage and necrosis may be present. Comparing H3 K27M mutant to WT tumors, there were significant differences in the following parameters: i) tumor localization (p = 0.001), ii) T2 signal intensity (p = 0.021), and iii) T1 signal homogeneity (p = 0.02). No significant imaging differences were found in any parameter between H3.1 and H3.3 K27M mutant tumors; however, H3.1 mutant tumors occurred at a younger age (p = 0.004). Considering spinal gliomas (n = 10) there were no significant imaging differences between the analyzed molecular groups. Conclusion With this study, we are the first to provide detailed MR imaging data on H3 K27M mutant pDMG with respect to molecular subgroup status in a large patient cohort. Our findings may support diagnosis and future targeted therapeutic trials of pDMG within the framework of the radiogenomics concept.
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Zhang, Peng, Tiantian Han, Yi Lu, Weijie Sun, Wanglong Deng, Guanghua Lu, Didi Guo, Xiaomin Li, and Fanfeng Bu. "Molecular characteristics of H3 K27M mutation gliomas in Chinese adults." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14018-e14018. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14018.
Анотація:
e14018 Background: Diffuse midline glioma H3 K27M–mutant is a specific entity added to the 2016 update of the WHO classification of CNS tumors. H3K27M-mutant gliomas are diagnosed primarily in children and adolescents with TP53 and/or ATRX mutations. However, the characteristics of H3 K27M-mutant gliomas in adults have not been explicitly described. Methods: We performed the 131-gene panel targeted sequencing on tumor samples from 33 adults H3 K27M-mutant gliomas( > 18 years) and 13 children and adolescents H3 K27M-mutant gliomas(≤18 years) in a CAP certified laboratory. Somatic mutations, copy number variations, and fusion genes were detected following the standard operating procedure (SOP). The MS-based assay measured MGMT promoter methylation. We calculated the tumor location and the median age in different cohorts. Results: In our adult cohort, 22/33（66.7%）had a midline location（spinal cord n = 2, thalamus n = 7, brainstem n = 6, cerebellum n = 3, pineal region n = 1, Basal ganglia region n = 3）, 6/33（18.1%）had a non-midline location (Lateral ventricle n = 2, Cerebral hemispheres n = 4). In the children and adolescents cohort, 11/13（84.6%）occurred in midline location, 1/13(7.7%) occurred in the Lateral ventricle. MGMT promoter methylation did not differ in adult and pediatric H3 K27M-mutant gliomas (12.1% vs. 0). H3 K27M-mutant adult gliomas significantly co-occurred with the NF1 mutation(P = 0.008937). The median age of H3 K27M-mutant adult gliomas with NF1 modification (13/33, 39.4%) is higher than the NF1 wild type (49 years vs. 38 years, P = 0.107), although the difference has no statistical significance. Conclusions: In Chinese adults, as in children, H3 K27M mutation gliomas are characterized by a constant midline location, low rate of MGMT promoter methylation. Inconsistently, H3 K27M mutant adult gliomas are featured by a higher rate of NF1 mutations. Our molecular profiling analysis revealed the H3 K27M mutation in adult gliomas. Our research suggests potential molecular pathogenesis of H3K27M mutant adult gliomas and identifies more therapeutic targets for precision medicine.
Тези доповідей конференцій з теми "Oncohistone H3.3 K27M":
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Harutyunyan, Ashot S., Brian Krug, Simon Papillon-Cavanagh, Haifen Chen, Shriya Deshmukh, Warren A. Cheung, Rui Li, et al. "Abstract B44: Identification of epigenomic changes induced by H3 K27M mutation in glioblastoma using patient-derived and CRISPR/Cas9 edited cell lines." In Abstracts: AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; December 3-6, 2017; Atlanta, Georgia. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.pedca17-b44.