OBJECTIVE: To analyze the clinical characteristics of patients with 11q23 rearrangement acute lymphoblastic leukemia (ALL) with non-KMT2A::AFF1 fusion genes. METHODS: The clinical data of 10 patients with KMT2A fusion gene positive and partner gene non-AFF1 ALL admitted to Henan Cancer Hospital from December 2016 to December 2024 were retrospectively summarized. The immunophenotype, molecular genetic characteristics, clinical manifestations and disease prognosis of these patients were analyzed. This research has been approved by the Medical Ethics Committee of Henan Cancer Hospital (Ethics No.: 2019342). RESULTS: Among the 10 patients, the fusion genes were KMT2A::MLLT1 in 7 cases, KMT2A::MLLT4, KMT2A::MLLT3 and KMT2A::MLLT10 in 1 case each. The European Group for the Immunological Classification of Leukemias (EGIL) classification included 6 cases of T-ALL, 2 cases of pro-B-ALL, 1 case of Common-B-ALL and 1 case of pre-B-ALL. 4 cases of B-ALL all expressed CD19, cCD79a, CD38 and HLA-DR, and some expressed CD34 and CD22, without expression or weak expression of CD10, without expression of CD20. One case was accompanied by myeloid marker CD15 expression. 6 cases of T-ALL all expressed CD34, CD7, most expressed CD38, and some expressed CD3, CD5, CD2, CD4 and CD8, and 1 case expressed CD4 and CD8 together. Chromosomal abnormalities were detected in 3 cases, 5 cases were positive for WT1 fusion gene, and 6 cases had gene alterations. 9 patients achieved the first complete remission (CR1) during chemotherapy, and 1 patient relapsed within 6 months after CR1. At the last follow up, 1 patient (the fusion gene was KMT2A::MLLT4) remained unrelieved. There were 2 cases of KMT2A rearrangement (KMT2A-r) persistent positive (+/+) and 8 cases of KMT2A-r negative (+/-). The overall survival (OS) rate and leukemia-free survival (LFS) rate of patients with KMT2A-r persistent positive were significantly lower than those of patients with negative change, and the differences were statistically significant (P values were all < 0.05). Among the 3 patients who received chemotherapy+allogeneic hematopoietic stem cell transplantation (allo-HSCT), no relapse was observed until the follow up day. The OS rate and LFS rate of patients with KMT2A::MLLT1 and chemotherapy+allo-HSCT were higher than those of non-KMT2A::MLLT1 and single chemotherapy patients, and the differences were not statistically significant (P values were all ≥ 0.05). There was no significant difference in OS rate and LFS rate between T-ALL and B-ALL patients (P values were all ≥ 0.05). The median LFS time of the 10 patients was 32 (0 ~ 100) months, and the median OS time was 36 (1 ~ 101) months. CONCLUSION The 11q23 rearrangement ALL with non-KMT2A::AFF1 transcript is mainly KMT2A::MLLT1, T-ALL is more common, and the rate of chromosomal karyotype detection is relatively low. Persistent positive KMT2A-r is unfavorable for patient survival, and allo-HSCT during the CR1 period may improve patient survival.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Female ; Male ; Myeloid-Lymphoid Leukemia Protein/genetics* ; Histone-Lysine N-Methyltransferase/genetics* ; Adult ; Adolescent ; Chromosomes, Human, Pair 11/genetics* ; Child ; Transcriptional Elongation Factors/genetics* ; Gene Rearrangement ; Oncogene Proteins, Fusion/genetics* ; Retrospective Studies ; Young Adult ; Middle Aged ; Prognosis ; Child, Preschool ; DNA-Binding Proteins/genetics*

OBJECTIVES: To explore the mechanism by which histone deacetylase 1 (HDAC1) regulates steroid-induced apoptosis of mouse osteocyte-like MLO-Y4 cells. METHODS: MLY-O4 cells were treated with 400 nmol/L trichostatin A (TSA) or 1 mmol/L dexamethasone for 24 h or transfected with a HDAC1-overexpressing vector prior to TSA or dexamethasone treatment. The changes in the expressions of HDAC1, SP1, cleaved caspase-3 and Bax, SP1 acetylation level, cell proliferation, and cell apoptosis were examined. The interaction between HDAC1 and SP1 was determined with immunoprecipitation assay and Western blotting. RESULTS: Treatment with dexamethasone significantly increased cell apoptosis, enhanced the expressions of cleaved caspase-3 and Bax, reduced HDAC1 expression, and suppressed proliferation of MLO-Y4 cells. Both TSA and dexamethasone obviously increased SP1 acetylation level and the expression of SP1 in MLO-Y4 cells. HDAC1 overexpression in the cells significantly attenuated the effect of TSA and dexamethasone, promoted cell proliferation, lowered the expressions of SP1, cleaved caspase-3 and Bax, and inhibited dexamethasone-induced cell apoptosis. Immunoprecipitation assay and Western blotting demonstrated the interaction between HDAC1 and SP1 in the cells. CONCLUSIONS HDAC1 inhibits dexamethasone-induced apoptosis and promotes proliferation of cultured mouse osteocytes by suppressing SP1 expression via promoting its deacetylation.
Animals ; Apoptosis/drug effects* ; Mice ; Histone Deacetylase 1/genetics* ; Osteocytes/drug effects* ; Sp1 Transcription Factor/metabolism* ; Acetylation ; Dexamethasone/pharmacology* ; Cell Proliferation/drug effects* ; Caspase 3/metabolism* ; Cell Line ; Hydroxamic Acids/pharmacology* ; bcl-2-Associated X Protein/metabolism*

Oral squamous cell carcinoma (OSCC) progresses from preneoplastic precursors via genetic and epigenetic alterations. Previous studies have focused on the treatment of terminally developed OSCC. However, the role of epigenetic regulators as therapeutic targets during the transition from preneoplastic precursors to OSCC has not been well studied. Our study identified lysine-specific demethylase 1 (LSD1) as a crucial promoter of OSCC, demonstrating that its knockout or pharmacological inhibition in mice reversed OSCC preneoplasia. LSD1 inhibition by SP2509 disrupted cell cycle, reduced immunosuppression, and enhanced CD4+ and CD8+ T-cell infiltration. In a feline model of spontaneous OSCC, a clinical LSD1 inhibitor (Seclidemstat or SP2577) was found to be safe and effectively inhibit the STAT3 network. Mechanistic studies revealed that LSD1 drives OSCC progression through STAT3 signaling, which is regulated by phosphorylation of the cell cycle mediator CDK7 and immunosuppressive CTLA4. Notably, LSD1 inhibition reduced the phosphorylation of CDK7 at Tyr170 and eIF4B at Ser422, offering insights into a novel mechanism by which LSD1 regulates the preneoplastic-to-OSCC transition. This study provides a deeper understanding of OSCC progression and highlights LSD1 as a potential therapeutic target for controlling OSCC progression from preneoplastic lesions.
STAT3 Transcription Factor/metabolism* ; Animals ; Histone Demethylases/genetics* ; Phosphorylation ; Mouth Neoplasms/immunology* ; Mice ; Carcinoma, Squamous Cell/immunology* ; Disease Progression ; Cyclin-Dependent Kinase-Activating Kinase ; Precancerous Conditions/metabolism* ; Humans ; Cyclin-Dependent Kinases/metabolism* ; Disease Models, Animal

Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis. However, mechanisms associated with stem cell senescence require further investigation. In this study, we conducted a proteomic analysis of human dental pulp stem cells (HDPSCs) obtained from individuals of various ages. Our findings showed that the expression of NUP62 was decreased in aged HDPSCs. We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo. Conversely, the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs. Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression, we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1. This, in turn, stimulates the transcription of the epigenetic enzyme NSD2. Finally, the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes (HMGA1, HMGA2, and SIRT6). Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
Humans ; Dental Pulp/cytology* ; Nuclear Pore Complex Proteins/genetics* ; Cellular Senescence/genetics* ; Stem Cells/metabolism* ; Epigenesis, Genetic ; Cell Proliferation ; Cell Differentiation ; Histone-Lysine N-Methyltransferase/metabolism* ; Cells, Cultured ; Cellular Reprogramming ; Cell Movement ; Proteomics

Tissue interactions play a crucial role in tooth development. Notably, extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential. Here, we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B. Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B, thereby regulating tooth development. An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice. In conclusion, this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization, which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.
Animals ; Extracellular Vesicles/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Swine ; MicroRNAs/metabolism* ; Mandible ; Mice, Nude ; Odontogenesis/physiology* ; Swine, Miniature ; Mice ; Cell Differentiation ; Cell Proliferation

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

Successful cloning through somatic cell nuclear transfer (SCNT) faces significant challenges due to epigenetic obstacles. Recent studies have highlighted the roles of H3K4me3 and H3K27me3 as potential contributors to these obstacles. However, the underlying mechanisms remain largely unclear. In this study, we generated genome-wide maps of H3K4me3 and H3K27me3 in mouse pre-implantation NT embryos. Our analysis revealed that aberrantly over-represented broad H3K4me3 domain and H3K27me3 signal lead to increased bivalent marks at gene promoters in NT embryos compared with naturally fertilized (NF) embryos at the 2-cell stage, which may link to relatively low levels of H3K36me3 in NT 2-cell embryos. Notably, the overexpression of Setd2, a H3K36me3 methyltransferase, successfully restored multiple epigenetic marks, including H3K36me3, H3K4me3, and H3K27me3. In addition, it reinstated the expression levels of ZGA-related genes by reestablishing H3K36me3 at gene body regions, which excluded H3K27me3 from bivalent promoters, ultimately improving cloning efficiency. These findings highlight the excessive bivalent state at gene promoters as a potent barrier and emphasize the removal of these barriers as a promising approach for achieving higher cloning efficiency.
Animals ; Mice ; Histone-Lysine N-Methyltransferase/biosynthesis* ; Histones/genetics* ; Nuclear Transfer Techniques ; Female ; Gene Expression Regulation, Developmental ; Promoter Regions, Genetic ; Epigenesis, Genetic ; Embryo, Mammalian/metabolism*

The p60 subunit of the chromatin assembly factor-1 complex, that is, chromatin assembly factor-1 subunit B (CHAF1B), is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal. CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy. However, its expression and clinical significance in lung squamous-cell carcinoma (LUSC) remain unclear. In this study, we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates. Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes. Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo. Furthermore, bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7 (SETD7) as a significant CHAF1B target gene. In addition, CHAF1B competitively binds to the SETD7 promoter region and represses its transcription. Altogether, these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.
Humans ; Lung Neoplasms/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Gene Expression Regulation, Neoplastic ; Disease Progression ; Cell Proliferation/genetics* ; Cell Line, Tumor ; Chromatin Assembly Factor-1/metabolism* ; Animals ; Mice ; Male ; Female

Sepsis is a life-threatening organ dysfunction caused by the host's dysregulated response to infection, with a complex pathogenesis and high mortality rate. Currently, there are no clear and effective treatment drugs available. Epigenetic modification serves as a major mechanism regulating gene expression under pathological and physiological conditions, and it has been shown to play a critical role in regulating the occurrence and development of sepsis. Histone acetylation modification, as a sophisticated epigenetic modification mechanism, plays a crucial regulatory role in many aspects of life. It can jointly regulate the acetylation status of histones through histone acetyltransferase (HAT) and histone deacetylase (HDAC), thereby changing DNA expression and dynamically regulating sepsis related gene expression at the epigenetic level. Previous studies have shown that histone acetylation can participate in the progression of sepsis by regulating inflammatory mediators, nuclear factor-ΚB (NF-ΚB) signaling pathway, autophagy, efferocytosis, ferroptosis, pyroptosis. These mechanisms are promising targets for novel sepsis treatments. In addition, with the deepening of research, it has been found that various selective/non selective histone deacetylase inhibitors (HDACI) can regulate histone acetylation status by acting on different HDAC targets, which has been shown to alleviate organ damage caused by sepsis and improve prognosis in septic animal models. This article further summarizes the role and potential applications of histone acetylation in sepsis, providing new ideas for the treatment of sepsis.
Sepsis/metabolism* ; Acetylation ; Humans ; Histones/metabolism* ; Histone Acetyltransferases/metabolism* ; Histone Deacetylase Inhibitors ; Epigenesis, Genetic ; Histone Deacetylases/metabolism* ; Signal Transduction ; NF-kappa B/metabolism* ; Animals

The HDAs (a subfamily of histone deacetylases), a class of Zn²⁺-dependent histone deacetylases, are highly homologous to the reduced potassium dependency 3 (RPD3) in yeast. HDAs extensively regulate chromosome stability, gene transcription, and protein activity by catalyzing the removal of acetyl group from histone and non-histone lysine residues. HDA-mediated deacetylation is essential for plant growth, development, and responses to abiotic stress. We review the research progress in HDAs regarding the discovery, structures, classification, deacetylation process, and roles in regulating plant responses to abiotic stress. Furthermore, this paper prospects the future research on HDAs, aiming to provide theoretical support for the research on epigenetic regulation mediated by HDAs.
Histone Deacetylases/classification* ; Zinc/metabolism* ; Stress, Physiological/physiology* ; Plants/genetics*