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1.
Blood ; 135(17): 1472-1483, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32315388

RESUMEN

Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Proteína Forkhead Box O1/metabolismo , Histona Desacetilasas/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Proteína Forkhead Box O1/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Represoras/genética , Secuencias Repetidas en Tándem , Células Tumorales Cultivadas , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
2.
J Immunol ; 195(4): 1849-57, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26179902

RESUMEN

Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4(+) T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect.


Asunto(s)
Enfermedad Injerto contra Huésped/etiología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Ácido Valproico/farmacología , Animales , Trasplante de Médula Ósea/efectos adversos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Ratones , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células TH1/citología , Células TH1/metabolismo , Células Th17/citología , Células Th17/metabolismo , Trasplante Homólogo , Ácido Valproico/administración & dosificación
3.
Artículo en Inglés | MEDLINE | ID: mdl-37804459

RESUMEN

PURPOSE: In this study, we developed a prognostic nomogram for esophageal squamous cell carcinoma (ESCC) patients. METHODS: Patients diagnosed with ESCC from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2017) and a local hospital were enrolled in this retrospective cohort study. Prognoses were analyzed using the R language software, and the predictive power of the model was then assessed by the Harrell concordance index (C-index) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: In total, 2915 ESCC patients from SEER database were divided into training and validation cohorts. Multivariate analysis revealed that sex, marital status, tumor-node-metastasis (TNM) stage, surgery, chemotherapy, and radiation all showed a significant association with overall survival (OS) and cancer-specific survival (CSS) (also with tumor grade). These characteristics were employed to build a nomogram. The C-index of the nomogram for OS and CSS prediction was 0.743 and 0.748 for the training cohort, which were superior to the predictive power of the 7th TNM staging system. The AUCs of the nomogram for predicting 2- and 5-year OS were 0.805 and 0.812, respectively, and the AUCs for CSS were 0.811 and 0.821, respectively. ROC and calibration curves of data from the SEER internal validation set and of data from our hospital showed that this model had good accuracy for predicting the prognosis of ESCC patient. CONCLUSION: The nomogram developed in this study provides a useful tool for accurately estimating OS and CSS for ESCC patients.

4.
Hematology ; 28(1): 2227491, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37367830

RESUMEN

OBJECTIVE: Necroptosis has been reported to play an important role in different cancers, including leukemia. However, biomarkers of necroptosis-related genes (NRGs) that help predict the prognosis of AML are still lacking. Our research aims to build a novel signature of NRGs that could enhance our understanding of the molecular heterogeneity in leukemia. METHOD: Gene expression profiles as well as clinical features were downloaded from TCGA and GEO databases. Data analysis were executed using R software version 4.2.1 and GraphPad Prism version 9.0.0. RESULT: Univariate cox regression and lasso regression were applied to identify survival-specific genes. Four genes including FADD, PLA2G4A, PYCARD and ZBP1 were considered as independent risk factors that affect the prognosis of patients. Risk scores were calculated according to the coefficient of four genes. Then clinical characteristics and risk scores were enrolled to construct a nomogram. CellMiner was also used to screen potential drugs and analyze the correlations between genes and drug sensitivity. CONCLUSION: In general, we established a signature of four genes related to necroptosis that could be helpful for future risk stratification in patients with AML.


Asunto(s)
Leucemia Mieloide Aguda , Necroptosis , Humanos , Necroptosis/genética , Leucemia Mieloide Aguda/genética , Bases de Datos Factuales , Nomogramas , Factores de Riesgo , Pronóstico
5.
J Oncol ; 2021: 4138575, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34567114

RESUMEN

OBJECTIVE: Recent years, there has been a rapid increase in the incidence of esophageal adenocarcinoma (EAC), while the prognosis for patients diagnosed remains poor and has slightly improved. METHODS: We extracted 6,466 cases with detailed demographical characteristics including age at diagnosis, sex, ethnicity, marital status, and clinical features, involving tumor grade and stage at diagnosis and treatment modalities (radiation therapy, chemotherapy, and surgery) from the Surveillance, Epidemiology, and End Results (SEER) (1975-2017) dataset. They were further randomly divided into the training and validating cohorts. Univariate and multivariate Cox analyses were conducted to determine significant variables for construction of nomogram. The predictive power of the model was then assessed by Harrell concordance index (C-index) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Multivariate analysis revealed that age, marital status, insurance, tumor grade, TNM stage, surgery, and chemotherapy all showed a significant association with overall survival (OS) and cancer-specific survival (CSS). These characteristics were employed to build a nomogram. Particularly, the discrimination of nomogram for OS and CSS prediction in the training set were excellent (C-index = 0.762, 95% CI: 0.754-0.770 and C-index = 0.774, 95% CI: 0.766-0.782). The AUC of the nomogram for predicting 2- and 5-year OS was 0.834 and 0.853 and CSS was 0.844 and 0.866. Similar results were observed in the internal validation set. CONCLUSION: We have successfully established a novel nomogram for predicting OS and CSS in EAC patients with good accuracy, which can help clinicians predict the survival of individual patient survival and provide optimal treatment strategies.

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