RESUMEN
The H3K4 methyltransferase SETD1A plays an essential role in both development and cancer. However, essential components involved in SETD1A chromatin binding remain unclear. Here, we discovered that BOD1L exhibits the highest correlated SETD1A co-dependency in human cancer cell lines. BOD1L knockout reduces leukemia cells in vitro and in vivo, and mimics the transcriptional profiles observed in SETD1A knockout cells. The loss of BOD1L immediately reduced SETD1A distribution at transcriptional start sites (TSS), induced transcriptional elongation defect, and increased the RNA polymerase II content at TSS; however, it did not reduce H3K4me3. The Shg1 domain of BOD1L has a DNA binding ability, and a tryptophan residue (W104) in the domain recruits SETD1A to chromatin through the association with SETD1A FLOS domain. In addition, the BOD1L-SETD1A complex associates with transcriptional regulators, including E2Fs. These results reveal that BOD1L mediates chromatin and SETD1A, and regulates the non-canonical function of SETD1A in transcription.
Asunto(s)
Cromatina , N-Metiltransferasa de Histona-Lisina , Histonas , Animales , Humanos , Ratones , Línea Celular Tumoral , Cromatina/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Leucemia/genética , Leucemia/metabolismo , Unión Proteica , Dominios Proteicos , ARN Polimerasa II/metabolismo , Sitio de Iniciación de la Transcripción , Transcripción GenéticaRESUMEN
The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain-mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3-binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A-binding and leukemia cell proliferation. Cell-cycle-specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.
Asunto(s)
Leucemia , Mitosis , Humanos , Mitosis/genética , Ciclinas/genética , Ciclinas/metabolismo , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Leucemia/genética , Proteínas de Unión a Poli-ADP-Ribosa/genéticaRESUMEN
Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer.
Asunto(s)
Leucemia , Humanos , Metabolómica , Regulación hacia Abajo , Reparación del ADN , ARN Polimerasa II , Hemo , N-Metiltransferasa de Histona-Lisina/genéticaAsunto(s)
Artritis Psoriásica/genética , Predisposición Genética a la Enfermedad , Psoriasis/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/epidemiología , Artritis Psoriásica/inmunología , Pueblo Asiatico/genética , Células Cultivadas , Niño , Femenino , Fibroblastos , Humanos , Japón/epidemiología , Queratinocitos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , Psoriasis/diagnóstico , Psoriasis/epidemiología , Psoriasis/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Transducción de Señal/inmunología , Piel/citología , Piel/inmunología , Piel/patología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Autoanticuerpos/análisis , Fármacos Dermatológicos/uso terapéutico , Pénfigo/diagnóstico , Psoriasis/diagnóstico , Anciano , Autoanticuerpos/inmunología , Desmogleína 1/inmunología , Errores Diagnósticos , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Pénfigo/sangre , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Índice de Severidad de la Enfermedad , Piel/inmunología , Piel/patología , Resultado del TratamientoRESUMEN
Cutaneous adverse drug reactions (cADR) should be appropriately managed in drug administration. LANSAP® , Rabecure® and VONOSAP® are currently used for Helicobacter pylori eradication therapy. Here, we examined the characteristics of cADR caused by these drugs using data from the Pharmaceuticals and Medical Devices Agency (PMDA). Periods subject to analyses were set according to the year of release of these drugs: (i) from 2008 to 2017 for LANSAP; (ii) from 2014 to 2017 for Rabecure; and (iii) 2017 for VONOSAP. Among all cADR reported to the PMDA, those attributed to LANSAP, Rabecure and VONOSAP accounted for 2.3%, 1.0% and 3.6% of cases, respectively. cADR occurred in patients aged in their 20s or older, with the oldest patients aged in their 60s. Numbers of male and female patients were 28 and 70 for LANSAP, eight and 14 for Rabecure and three and 16 for VONOSAP, respectively. Statistical analyses revealed significant sex differences for LANSAP (P = 0.022) and VONOSAP (P = 0.012), but not for Rabecure (P = 0.729). LANSAP, Rabecure or VONOSAP caused erythema multiforme in the largest population of patients and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in three patients. Ratios of SJS/TEN were 0.0-5.3% for LANSAP, Rabecure or VONOSAP, but 11.5-44.8% for the corresponding single constituent drugs other than vonoprazan. In conclusion, female sex appears to represent a risk factor for cADR attributed to H. pylori eradication therapy using LANSAP or VONOSAP, although H. pylori eradication therapy without these drugs rarely causes severe cADR.
Asunto(s)
Antibacterianos/efectos adversos , Eritema Multiforme/inducido químicamente , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Inhibidores de la Bomba de Protones/efectos adversos , Síndrome de Stevens-Johnson/etiología , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Amoxicilina/efectos adversos , Claritromicina/efectos adversos , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Lansoprazol/efectos adversos , Masculino , Persona de Mediana Edad , Pirroles/efectos adversos , Rabeprazol/efectos adversos , Factores Sexuales , Sulfonamidas/efectos adversosAsunto(s)
Antifúngicos/efectos adversos , Queratosis Actínica/diagnóstico , Trastornos por Fotosensibilidad/diagnóstico , Rayos Ultravioleta/efectos adversos , Voriconazol/efectos adversos , Anciano , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Humanos , Queratosis Actínica/etiología , Queratosis Actínica/patología , Masculino , Enfermedades de los Senos Paranasales/tratamiento farmacológico , Enfermedades de los Senos Paranasales/microbiología , Trastornos por Fotosensibilidad/etiología , Trastornos por Fotosensibilidad/patología , Piel/efectos de los fármacos , Piel/patología , Piel/efectos de la radiación , Pruebas CutáneasAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Mucina-1/sangre , Psoriasis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Biomarcadores/sangre , Biomarcadores/metabolismo , Humanos , Interleucina-17/antagonistas & inhibidores , Estudios Longitudinales , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Mucina-1/metabolismo , Psoriasis/sangre , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Estudios RetrospectivosAsunto(s)
Antivirales/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Ustekinumab/uso terapéutico , Anciano , Carbamatos , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/sangre , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Imidazoles/uso terapéutico , Isoquinolinas/uso terapéutico , Masculino , Psoriasis/complicaciones , Psoriasis/diagnóstico , Pirrolidinas , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Inducción de Remisión/métodos , Índice de Severidad de la Enfermedad , Sulfonamidas/uso terapéutico , Valina/análogos & derivadosRESUMEN
BACKGROUND: Allergic contact dermatitis (ACD), which is accelerated by interferon (IFN)-γ and suppressed by interleukin (IL)-10 as regulators, is generally self-limited after removal of the contact allergen. Adipose tissue-derived multipotent mesenchymal stem cells (ASCs) potentially exert immunomodulatory effects. Considering that subcutaneous adipose tissue is located close to the site of ACD and includes mesenchymal stem cells (MSCs), the MSCs in adipose tissue could contribute to the self-limiting course of ACD. OBJECTIVE: The aims of the present study were to elucidate the effects of MSCs in adipose tissue on ACD and to examine any cytokine-mediated mechanisms involved. METHODS: Ear thickness in a C57BL/6 mouse model of ACD using contact hypersensitivity (CHS) elicited by 2,4,6-trinitro-1-chlorobenzene was evaluated as a marker of inflammation level. Five and nine mice were injected with ASCs and phosphate-buffered saline (PBS), respectively. After ASC or PBS injection, real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed. RESULTS: Histology showed that CHS was self-limited and ear thickness was suppressed by ASCs in a dose-dependent manner. IFN-γ expression in the elicited skin site and regional lymph nodes was significantly lower in ASC-treated mice than in control mice. IL-10 expression did not differ between treated and control mice. The suppressive effects of ASCs on CHS response did not differ between IL-10 knock-out C57BL/6 mice and wild-type mice. CONCLUSION: The present findings suggest that MSCs in adipose tissue may contribute to the self-limiting course of ACD through decreased expression of IFN-γ, but not through increased expression of IL-10.
RESUMEN
Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.
Asunto(s)
Productos Biológicos/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Sustitución de Medicamentos/efectos adversos , Psoriasis/tratamiento farmacológico , Adalimumab/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Infliximab/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Resultado del Tratamiento , Ustekinumab/uso terapéuticoAsunto(s)
Dermatitis Exfoliativa/radioterapia , Enfermedad Injerto contra Huésped/radioterapia , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Terapia Ultravioleta , Adulto , Dermatitis Exfoliativa/etiología , Dermatitis Exfoliativa/patología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Terapia Ultravioleta/métodosRESUMEN
BACKGROUNDS: Interleukin (IL)-10-producing regulatory B cells (B10 cells) have been shown to ameliorate psoriasis in mice. Human B10 progenitor cells are characterized as CD19(+)CD24(hi)CD38(hi) B cells that exert their regulatory functions via the production of IL-10. However, the role of B10 cells in the pathogenesis of psoriasis remains unclear. OBJECTIVES: We examined B10 cells in patients with psoriasis and healthy controls. METHODS: Peripheral blood mononuclear cells were isolated from psoriasis patients without a history of receiving any immunosuppressants during the 6-month period before enrollment in the study. Using flow cytometry, we determined the frequencies of blood B cell subsets, B10 progenitor cells, and B10 cells for 31 patients with psoriasis and 26 healthy controls. RESULTS: Both psoriasis patients and healthy controls showed similar frequencies of total B cells, IgD(+)CD27(-) naïve B cells, and IgD(-)CD27(+) memory B cells. However, the frequency of CD19(+)CD24(hi)CD38(hi) B10 progenitor cells was significantly higher in patients with psoriasis than in the healthy controls. In contrast, the frequency of B10 cells in patients with psoriasis was significantly lower than that in healthy controls. Furthermore, treatment with immunosuppressants resulted in a decrease in B10 progenitor cells and an increase in B10 cells. CONCLUSION: B10 progenitor cells were increased, while IL-10-producing regulatory B10 cells were decreased in patients with psoriasis, suggesting that B10 cells may be functionally impaired in patients with psoriasis.
Asunto(s)
Linfocitos B Reguladores/metabolismo , Interleucina-10/sangre , Psoriasis/sangre , Antígenos CD/sangre , Linfocitos B Reguladores/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Células Cultivadas , Regulación hacia Abajo , Citometría de Flujo , Humanos , Memoria Inmunológica , Inmunofenotipificación/métodos , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Fenotipo , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Antinucleares/efectos de los fármacos , Fármacos Dermatológicos/uso terapéutico , Psoriasis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/uso terapéutico , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Estudios de Seguimiento , Humanos , Infliximab/uso terapéutico , Japón , Masculino , Persona de Mediana Edad , Psoriasis/sangre , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Ustekinumab/uso terapéuticoRESUMEN
Psoriatic arthritis (PsA), a seronegative arthropathy, may often result in progressive joint damage without treatment, leading to disability and impaired quality of life. Early therapeutic intervention of PsA is therefore crucial before the development of irreversible joint damage. Because psoriatic skin lesions generally precede the onset of PsA, dermatologists occupy an important position in treating patients with early PsA. This study aimed to evaluate the efficacy of adalimumab in treating joint disease in patients with PsA, using the PsA magnetic resonance imaging scoring system (PsAMRIS). Five adult Japanese male patients with active PsA were treated with adalimumab. Magnetic resonance imaging was obtained at baseline and 8-32 weeks with 2-3 time points following adalimumab treatment and assessed using PsAMRIS. Adalimumab treatment markedly improved clinical symptoms and disease activities of joint disease, which was confirmed by the reduction of PsAMRIS scores in all patients. Bone marrow edema and periarticular inflammation, reflecting the presence of enthesitis, were dramatically improved at week 8, while improvement of synovitis and flexor tenosynovitis was observed later, at week 24 or 32. However, bone erosion was not improved by adalimumab treatment during the follow-up period. These results indicate that adalimumab treatment is associated with dramatic improvement of enthesitis in patients with PsA, whereas bone erosion may be resistant to such treatment. PsAMRIS appears to be useful for the evaluation of treatment efficacy in PsA.