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Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.
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Neoplasias , Cuerpos Nucleares , Humanos , Dominios Proteicos , Cromatina/genética , Mutación , Neoplasias/genéticaRESUMEN
Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.
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Linaje de la Célula , Cromatina/genética , Proteínas de Unión al ADN/metabolismo , Mutación con Ganancia de Función , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Células HEK293 , Humanos , Ratones , Nefronas/metabolismo , Nefronas/patología , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.
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Resistencia a Antineoplásicos , Linfoma de Células B Grandes Difuso , Humanos , Resistencia a Antineoplásicos/genética , Ubiquitina , Proteómica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Rituximab/uso terapéutico , Vincristina , Ciclofosfamida , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Prednisona , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor Notch2/genéticaRESUMEN
Recognition of histone covalent modifications by chromatin-binding protein modules ("readers") constitutes a major mechanism for epigenetic regulation, typified by bromodomains that bind acetyllysine. Non-acetyl histone lysine acylations (e.g., crotonylation, butyrylation, propionylation) have been recently identified, but readers that prefer these acylations have not been characterized. Here we report that the AF9 YEATS domain displays selectively higher binding affinity for crotonyllysine over acetyllysine. Structural studies revealed an extended aromatic sandwiching cage with crotonyl specificity arising from π-aromatic and hydrophobic interactions between crotonyl and aromatic rings. These features are conserved among the YEATS, but not the bromodomains. Using a cell-based model, we showed that AF9 co-localizes with crotonylated histone H3 and positively regulates gene expression in a YEATS domain-dependent manner. Our studies define the evolutionarily conserved YEATS domain as a family of crotonyllysine readers and specifically demonstrate that the YEATS domain of AF9 directly links histone crotonylation to active transcription.
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Crotonatos/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Procesamiento Proteico-Postraduccional , Transcripción Genética , Activación Transcripcional , Acetilación , Animales , Sitios de Unión , Ensamble y Desensamble de Cromatina , Epigénesis Genética , Células HEK293 , Histonas/química , Histonas/genética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lisina , Ratones , Modelos Moleculares , Mutación , Proteínas Nucleares/química , Proteínas Nucleares/genética , Dominios Proteicos , Células RAW 264.7 , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción , TransfecciónRESUMEN
Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.
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Acetilación , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Oncogenes/genética , Factores de Elongación Transcripcional/metabolismo , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Epigénesis Genética , Femenino , Edición Génica , Histonas/química , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Lisina/metabolismo , Ratones , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Dominios Proteicos , ARN Polimerasa II/metabolismo , Transcripción Genética , Factores de Elongación Transcripcional/química , Factores de Elongación Transcripcional/deficiencia , Factores de Elongación Transcripcional/genéticaRESUMEN
Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in normal physiology and disease pathogenesis. Here we report the development of the first class of chemical probes of YEATS domains, newly identified 'readers' of histone lysine acetylation (Kac) and crotonylation (Kcr). Guided by the structural analysis of a YEATS-Kcr complex, we developed a series of peptide-based inhibitors of YEATS domains by targeting a unique π-π-π stacking interaction at the proteins' Kcr recognition site. Further structure optimization resulted in the selective inhibitors preferentially binding to individual YEATS-containing proteins including AF9 and ENL with submicromolar affinities. We demonstrate that one of the ENL YEATS-selective inhibitors, XL-13m, engages with endogenous ENL, perturbs the recruitment of ENL onto chromatin, and synergizes the BET and DOT1L inhibition-induced downregulation of oncogenes in MLL-rearranged acute leukemia.
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Diseño de Fármacos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/química , Péptidos/farmacología , Factores de Elongación Transcripcional/antagonistas & inhibidores , Azepinas/farmacología , Línea Celular , Cromatina/metabolismo , Cristalografía por Rayos X , Regulación de la Expresión Génica/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina , Humanos , Lisina/metabolismo , Metiltransferasas/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Péptidos/química , Dominios Proteicos , Procesamiento Proteico-Postraduccional , Relación Estructura-Actividad , Factores de Elongación Transcripcional/química , Factores de Elongación Transcripcional/metabolismo , Triazoles/farmacologíaRESUMEN
OBJECTIVE: To observe the efficacy and safety of Danlong Oral Liquid (DOL) combined Western medicine (WM) in treating mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset. METHODS: Totally 480 mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset were randomly assigned to two groups in the ratio 3:1, the treatment group (360 cases) and the control group (120 cases). All patients received basic WM treatment. Patients in the treatment group took DOL, 10 mL each time, 3 times per day for 7 days in total, while those in the control group took Kechuanning Oral Liquid (KOL) , 10 mL each time, 3 times per day for 7 days in total. Efficacy for asthma symptoms, lung functions and scores of TCM syndrome and/or main symptoms were evaluated. RESULTS: The percentage of clinical control and significant effectiveness of asthma symptoms in the treatment group was significantly higher than that of the control group (77.36% vs 56.07%, P < 0.01). The percentage of clinical control and significant effectiveness of lung functions in the treatment group was significantly higher than that of the control group (74.28% vs 50.00%, P < 0.01). The anterior-posterior difference in scores of TCM syndrome was significantly superior in the treatment group than in the control group (-11.26 ± 4.70 vs -9.21 ± 5.09, P < 0.01). The anterior-posterior difference in scores of main symptoms was significantly better in the treatment group than in the control group (-6.58 ± 3.08 vs -5.16 ± 3.45, P < 0.01). The incidence of adverse reactions was significantly lower in the treatment group than in the control group [1.73% (6/346 cases) vs 10.17% (12/118 cases) , P < 0.05]. CONCLUSION: DOL combined WM was superior to KOL in treating mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Antiasmáticos/administración & dosificación , Investigación Biomédica , Quimioterapia Combinada/métodos , Medicamentos Herbarios Chinos/administración & dosificación , Calor , Humanos , Pulmón , Medicina Tradicional China , Fitoterapia , Ruidos Respiratorios , SíndromeRESUMEN
Precise gene expression, crucial for normal development and health, depends on the co-ordinated assembly and function of various factors within the crowded nucleus. Recent evidence suggests that this process is in part regulated by mesoscale compartmentalization and concentration of transcriptional components within condensates, offering a new perspective on gene regulation. Dysregulation of transcriptional condensates is increasingly associated with diseases, indicating a potential role in pathogenesis. In this mini-review, we provide a concise overview of the current understanding of the formation and function of transcriptional condensates, with a specific focus on recent advances in their dysregulation and implications in diseases, notably cancer. We also address limitations in the field and highlight open questions for future research.
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Regulación de la Expresión Génica , Neoplasias , Transcripción Genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Regulación de la Expresión Génica/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL's histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
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Diferenciación Celular , Riñón , Mutación , Análisis de la Célula Individual , Animales , Ratones , Riñón/metabolismo , Riñón/patología , Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión Génica , Cromatina/metabolismo , Epigénesis Genética , Tumor de Wilms/genética , Tumor de Wilms/patología , Tumor de Wilms/metabolismo , Histonas/metabolismo , Acetilación , Humanos , Organogénesis/genética , Vía de Señalización Wnt/genética , Nefronas/metabolismo , Nefronas/patología , Nefronas/embriología , Transcriptoma/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Femenino , Masculino , MultiómicaRESUMEN
Cell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly the HOX clusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolution in vivo . It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.
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Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.
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Mutación , Animales , Ratones , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Carcinogénesis/genética , Humanos , Código de Histonas , Histonas/metabolismoRESUMEN
Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.
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Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. SIGNIFICANCE: NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.
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Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , Cromatina/genéticaRESUMEN
The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Ciclofilinas/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Proteína p53 Supresora de Tumor/genética , Necrosis/genética , Neoplasias Pulmonares/genéticaRESUMEN
This study was designed to determine the therapeutic efficacy and safety of the Shi-cha capsule, a Chinese herbal formula, in the treatment of patients with wind-cold type common cold. In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with wind-cold type common cold received 0.6 g of Shi-cha capsule plus 0.6 g placebo (group A), 1.2 g of Shi-cha capsule (group B), or 1.2 g placebo (group C), three times daily for 3 days and followed up to 10 days. The primary end point was all symptom duration. The secondary end points were main symptom duration, minor symptom duration, the changes in cumulative symptom score, main symptom score, and minor symptom score 4 days after the treatment, as well as adverse events. A total of 377 patients were recruited and 360 met the inclusive criteria; 120 patients constituted each treatment group. Compared with patients in group C, patients in groups A and B had significant improvement in the all symptom duration, main symptom duration, minor symptom duration, as well as change from baseline of cumulative symptom score, main symptom score, and minor symptom score at day 4. The symptom durations and scores showed slight superiority of group B over group A, although these differences were not statistically significant. There were no differences in adverse events. The Shi-cha capsule is efficacious and safe for the treatment of patients with wind-cold type common cold. Larger trials are required to fully assess the benefits and safety of this treatment for common cold.
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Background: Re Du Ning, a traditional Chinese medicine injection, has been widely used for the treatment of chronic obstructive pulmonary disease, although without established systematic review evidence. This systematic review aimed to assess the efficacy and safety of Re Du Ning in the treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Methods: We searched seven databases (PubMed, Embase, the Cochrane Library, SinoMed, CNKI, WanFang, and the Chinese Clinical Trial Registry) up to November 1, 2021, to identify randomized controlled trials of Re Du Ning for AECOPD. Two researchers independently carried out literature screening and data extraction. Effects were measured by risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs). The meta-analysis was completed by RevMan 5.4 software. Results: Twenty-six studies met the eligibility criteria, with a total of 2284 patients. The findings of the meta-analysis indicated that the response rate of the experimental group was higher than that of the control group: RR = 1.14% and 95% CI: (1.09, 1.19). Significantly greater improvements in pulmonary function: FEV1: MD = 0.28 L, 95% CI: (0.20, 0.36); FEV1/FVC: MD = 8.63%, 95% CI: (4.68, 12.59); T-lymphocyte counts: CD4: MD = 6%, 95% CI: (2.44, 9.56); CD3: MD = 10.42%, 95% CI: (8.6, 12.24); CD4/CD8: MD = 0.38%, 95% CI: (0.32, 0.43); acid/base imbalance: PH: MD = 0.05, 95% CI: (0.01, 0.10); PaO2: MD = 9.02 mmHg, 95% CI: (11.11, 0.10), p=0.005; C-reactive protein: MD = -6.65 mg/L, 95% CI: (-10.97, -2.34); and PCT: MD = -0.28 µg/L, 95% (CI: -0.41, -0.15) were observed in patients receiving Re Du Ning compared with those receiving the control treatment. Re Du Ning did not significantly change the carbon dioxide partial pressure. All reported adverse reactions were mild. Conclusion: Re Du Ning injection, as a complementary therapy to routine treatment, has better efficacy than Western medicine alone in relieving clinical symptoms, delaying pulmonary function decline, and improving inflammation indicators for AECOPD, with good safety. The evidence was limited by a lack of high-quality RCTs.
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Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.
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Neoplasias de la Mama , Presentación de Antígeno , Neoplasias de la Mama/tratamiento farmacológico , Endonucleasas/metabolismo , Femenino , Humanos , Proteínas de la Membrana/metabolismo , Nucleasa Microcócica/metabolismo , Proteínas Nucleares/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.
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Endonucleasas/metabolismo , Proteínas de la Membrana/metabolismo , Nucleasa Microcócica , Proteínas de Unión al ARN/metabolismo , Neoplasias de la Mama Triple Negativas , Animales , Moléculas de Adhesión Celular/genética , Humanos , Proteínas de la Membrana/genética , Ratones , Proteínas de Unión al ARN/genética , Factores de TranscripciónRESUMEN
Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. SIGNIFICANCE: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587.
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Leucemia Mieloide Aguda , Oncogenes , Cromatina/genética , Epigénesis Genética , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de Neoplasias , Proteínas Nucleares , Factores de TranscripciónRESUMEN
The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.