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Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.
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Compuestos de Anilina , Proteínas de Ciclo Celular , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metformina , Mutación , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Pirazinas , Transducción de Señal , Tirosina Quinasa 3 Similar a fms , Metformina/farmacología , Metformina/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Humanos , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Transducción de Señal/efectos de los fármacos , Pirazinas/farmacología , Pirazinas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Ratones , Mutación/genética , Línea Celular Tumoral , Tiofenos/farmacología , Tiofenos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/genética , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Multiple myeloma (MM) stands as a prevalent hematological malignancy, primarily incurable, originating from plasma cell clones. MM's progression encompasses genetic abnormalities and disruptions in the bone marrow microenvironment, leading to tumor proliferation, immune dysfunction, and compromised treatment outcomes. Emerging evidence highlights the critical role of regulatory T cells (Tregs) in MM progression, suggesting that targeting Tregs could enhance immune functionality and treatment efficacy. In this study, a notable increase in Treg proportions within MM patients' bone marrow (BM) compared to healthy individuals is observed. Additionally, it is found that the bromodomain and extraterminal domain (BET) inhibitor JQ1 selectively diminishes Treg percentages in MM patients' BM and reduces TGF-ß1-induced Tregs. This reduction occurs via inhibiting cell viability and promoting apoptosis. RNA sequencing further indicates that JQ1's inhibitory impact on Tregs likely involves upregulating STAT3 and suppressing PD-1 expression. Collectively, these findings suggest JQ1's potential to modulate Tregs, bolstering the immune response in MM and introducing a promising avenue for MM immunotherapy.
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Azepinas , Mieloma Múltiple , Receptor de Muerte Celular Programada 1 , Factor de Transcripción STAT3 , Linfocitos T Reguladores , Triazoles , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Mieloma Múltiple/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Humanos , Azepinas/farmacología , Azepinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Masculino , Persona de Mediana Edad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas que Contienen Bromodominio , ProteínasRESUMEN
BACKGROUND: Molecular genetics serve a critical role in constructing risk stratification for hematological malignancies, but T-cell lymphoma (TCL) still lacks molecular genetic information for supplement risk stratification in predicting the prognosis of TCL patients. In the present study, we characterized the mutation patterns of B-cell leukemia/lymphoma 11B gene (BCL11B) and its prognostic importance in TCL patients. METHODS: BCL11B mutations were characterized based on the data from two datasets, one is from our clinical center (GDPH dataset, n = 79) and the other is from COSMIC dataset (n = 154). RESULTS: The overall mutation rate of BCL11B was 6.4% (15/233) in TCL, and there were no hotspot mutation sites in TCL. Among these mutations, the missense and splice site mutation were significantly prominent. Moreover, TCL patients harboring BCL11B mutations had a favorable overall survival (OS) in our center (GDPH dataset) (adjusted hazard ratio [HR] = .001, p = 0.109), although there were not yet significantly statistical at this point. In addition, TCL patients harboring BCL11B mutation had a longer 5-year restricted mean survival time (RMST) than those without a BCL11B mutation (60 vs. 32 months). Notably, BCL11B mutations were not associated with TCL entities having better prognosis. CONCLUSIONS: BCL11B mutations were associated with favorable clinical outcome for TCL patients; it might be considered as a novel biomarker for TCL prognostic stratification.
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Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Proteínas Supresoras de Tumor/genética , Proteínas Represoras/genética , Mutación , Linfoma de Células T/genética , Factores de TranscripciónRESUMEN
Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.
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Desoxicitidina , Neoplasias Pancreáticas , Humanos , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Gemcitabina , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Caspasa 1 , Terapia Combinada , Línea Celular TumoralRESUMEN
Exome sequencing of in situ tumor samples reveals that mutated genes can predict the prognosis of patients with T-cell lymphoma (TCL). However, how tumor mutation burden (TMB) derived from circulating tumor DNA (ctDNA) may stratify TCL patients remains unclear.The plasma ctDNA of 79 newly diagnosed TCL patients from the clinical center is used for targeted exome sequencing, and the exome data of 4035 TCL patients from the Catalogue of Somatic Mutations in Cancer (COSMIC) database is obtained for comparison analysis.TCL patients with higher TMB, as evaluated with a panel of 120 genes (panel-TMB120), are associated with poor prognosis. More importantly, COX regression analysis identifies a subset of 13 genes in panel-TMB120, including AP3B1 (Adaptor related protein complex 3 subunit beta 1), ATM (Ataxia-telangiectasia mutated), BCL6 (B cell lymphoma 6), BRAF (B-Raf proto-oncogene, serine/threonine kinase), CDKN2B (Cyclin dependent kinase inhibitor 2B), EPCAM (Epithelial cell adhesion molecule), FBXO11 (F-box protein 11), JAK1 (Janus kinase 1), MDM2 (Murine double minute 2), NF1 (Neurofibromin 1), STAT5B (Signal transducer and activator of transcription 5B), STAT6 (Signal transducer and activator of transcription 6), and TET2 (Tet methylcytosine dioxygenase 2), which are significantly associated with prognosis. Specifically, higher TMB values calculated with these 13 genes (panel-TMB13) are able to significantly predict unfavorable prognosis for these patients. Together, panel-TMB13 and the International Prognostic Index (IPI) are used for risk stratification.Panel-TMB13 is identified, which can predict poor prognosis for TCL patients carrying higher panel-TMB13 scores and suggest that panel-TMB13 may be a potential biomarker for supplement risk stratification of TCL patients.
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Proteínas F-Box , Linfoma de Células T Periférico , Neoplasias , Humanos , Animales , Ratones , Biomarcadores de Tumor/genética , Proteínas Serina-Treonina Quinasas , Pronóstico , Proteína-Arginina N-MetiltransferasasRESUMEN
Drug resistance and poor treatment response are major obstacles to the effective treatment of acute myeloid leukemia (AML). A deeper understanding of the mechanisms regulating drug resistance and response genes in AML is therefore urgently needed. Our previous research has highlighted the important role of nuclear factor E2-related factor 2 (NRF2) in AML, where it plays a critical role in detoxifying reactive oxygen species and influencing sensitivity to chemotherapy. In this study, we identify a core set of direct NRF2 targets that are involved in ferroptosis, a novel form of cell death. Of particular interest, we find that glutathione peroxidase 4 (GPX4) is a key ferroptosis gene that is consistently upregulated in AML, and high expression of GPX4 is associated with poor prognosis for AML patients. Importantly, simultaneous inhibition of NRF2 with ML385 and GPX4 with FIN56 or RSL3 synergistically targets AML cells, triggering ferroptosis. Treatment with ML385 + FIN56/RSL3 resulted in a marked reduction in NRF2 and GPX4 expression. Furthermore, NRF2 knockdown enhanced the sensitivity of AML cells to the ferroptosis inducers. Taken together, our results suggest that combination therapy targeting both NRF2 and GPX4 may represent a promising approach for the treatment of AML.
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Caspase-1 (CASP1)-mediated classical pyroptosis plays a key role in cancer development and management, however, the role of CASP1 and its regulation has not yet been documented for acute promyelocytic leukemia (APL). Here, we found that CASP1/GSDMD had lower expression in patients with APL and most other subtypes of primary de novo acute myeloid leukemia (AML) and was increased in all-trans-retinoic acid (ATRA)-treated APL cells. We showed that ATRA increases and activates CASP1 to trigger the pyroptosis and differentiation of APL cells. Mechanistically, ATRA could induce CASP1 expression via the IFNγ/STAT1 pathway in APL cells. In conclusion, ATRA-induced activation of CASP1 may serve as a suppressor in APL progression, as it triggers pyroptotic cell death and differentiation.
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Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/genética , Piroptosis , Caspasa 1 , Tretinoina/farmacología , Diferenciación CelularRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) is an aggressive heterogeneous hematological malignancy with remarkably heterogeneous outcomes. This study aimed to identify potential biomarkers for AML risk stratification via analysis of gene expression profiles. METHODS: RNA sequencing data from 167 adult AML patients in the Cancer Genome Atlas (TCGA) database were obtained for overall survival (OS) analysis, and 52 bone marrow (BM) samples from our clinical center were used for validation. Additionally, siRNA was used to investigate the role of prognostic genes in the apoptosis and proliferation of AML cells. RESULTS: Co-expression of 103 long non-coding RNAs (lncRNAs) and mRNAs in the red module that were positively correlated with European Leukemia Network (ELN) risk stratification and age was identified by weighted gene co-expression network analysis (WGCNA). After screening by uni- and multivariate Cox regression, Kaplan-Meier survival, and protein-protein interaction analysis, four genes including the lncRNA LOC541471, GDAP1, SOD1, and STK25 were incorporated into calculating a risk score from coefficients of the multivariate Cox regression model. Notably, GDAP1 expression was the greatest contributor to OS among the four genes. Interestingly, the risk score, ELN risk stratification, and age were independent prognostic factors for AML patients, and a nomogram model constructed with these factors could illustrate and personalize the 1-, 3-, and 5-year OS rates of AML patients. The calibration and time-dependent receiver operating characteristic curves (ROCs) suggested that the nomogram had a good predictive performance. Furthermore, new risk stratification was developed for AML patients based on the nomogram model. Importantly, knockdown of LOC541471, GDPA1, SOD1, or STK25 promoted apoptosis and inhibited the proliferation of THP-1 cells compared to controls. CONCLUSIONS: High expression of LOC541471, GDAP1, SOD1, and STK25 may be biomarkers for risk stratification of AML patients, which may provide novel insight into evaluating prognosis, monitoring progression, and designing combinational targeted therapies.
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Leucemia Mieloide Aguda , ARN Largo no Codificante , Adulto , Humanos , Superóxido Dismutasa-1 , Biomarcadores de Tumor/metabolismo , Leucemia Mieloide Aguda/patología , Pronóstico , Perfilación de la Expresión Génica , ARN Largo no Codificante/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
BACKGROUND: It is imperative to explore potential biomarkers for predicting clinical outcome and developing targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). This study aimed to investigate the mutation patterns of tumor necrosis factor-alpha-inducing protein 3 (TNFAIP3, also known as A20) and its role in the prognosis of T-ALL patients. METHODS: Polymerase chain reaction (PCR) and Sanger sequencing data from T-ALL (n = 49, JNU) and targeted sequencing data from T-ALL (n = 54, NFH) in our clinical center and a publicly available dataset (n = 121, PRJCA002270), were used to detect TNFAIP3 mutation. RESULTS: Three TNFAIP3 single nucleotide polymorphisms (SNPs; g.3033 C > T, g.3910 G > A, and g.3904 A > G) were detected in T-ALL in the JNU dataset, and g.3033 C > T accounted for the highest proportion, reaching 60% (6/10). Interestingly, TNFAIP3 mutation mainly occurred in adults but not pediatric patients in all three datasets (JNU, NFH, and PRJCA002270). T-ALL patients carrying a TNFAIP3 mutation were associated with a trend of poor overall survival (OS) (p = 0.092). Moreover, TNFAIP3 mutation was also an independent factor for OS for T-ALL patients (p = 0.008). Further subgroup analysis suggested that TNFAIP3 mutation predicted poor OS for T-ALL patients who underwent chemotherapy only (p < 0.001), and it was positively correlated with high risk and early T-cell precursor ALL (ETP-ALL) in two independent validation datasets (NFH and PRJCA002270). CONCLUSION: TNFAIP3 mutation mainly occurs in adult T-ALL patients, and it was associated with adverse clinical outcomes for T-ALL patients; thus, it might be a biomarker for prognostic stratification.
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Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutación , Pronóstico , Polimorfismo de Nucleótido Simple , Linfocitos T , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Regulated cell death (RCD) is essential for maintaining cell homeostasis and preventing diseases. Besides classical apoptosis, several novel nonapoptotic forms of RCD including NETosis, pyroptosis, ferroptosis, and cuproptosis have been reported and are increasingly being implicated in various cancers and inflammation. Disulfiram (DSF), an aldehyde dehydrogenase inhibitor, has been used clinically for decades as an anti-alcoholic drug. New studies have shown that DSF possesses potent anti-inflammatory and anti-cancer effects by regulating these new types of RCD. Here, we summarize the mechanisms and discuss the potential application of DSF in the treatment of cancers and inflammatory diseases.
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Background: T-cell malignancies (TCMs), including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are highly aggressive and have a poor prognosis. To further understand prognostic stratifications and to design targeted therapies, this study aims to explore novel, potential biomarkers based on alterations in immune costimulatory molecules (CMs) for TCMs. Methods: Peripheral blood from 25 de novo T-ALL patients in our clinical center and transcriptome data from 131 to 162 patients with peripheral TCL (PTCL) from the GSE19069 and GSE58445 dataset, respectively, were obtained to assess the expression levels of CMs and their prognostic significance. Results: Seven CMs were associated with overall survival (OS). Among these CMs, CD5 and CD6 had the highest pairwise positive correlation (R = 0.69). CD5 and CD6 were significantly down-regulated in TCM patients compared with healthy individuals (HIs), and lower CD5 and CD6 expression was associated with poor OS for both T-ALL and TCL patients, particularly for patients greater than 60 years old. Furthermore, CD5 was positively correlated with CD6 in TCM patients. Compared with patients who were CD5highCD6high, T-ALL and TCL patients who were CD5lowCD6low had poor OS. Importantly, CD5highCD6high was an independent prognostic predictor for OS in T-ALL (HR = 0.39, 95% CI: 0.23-0.65, P < 0.001) and TCL (HR = 0.35, 95% CI: 0.19-0.62, P < 0.001) patients. Conclusions: Low expression of CD5 and CD6 was associated with poor OS for TCM patients, and this may be a potential immune biomarker panel for prognostic stratification of TCM patients.
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Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.
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Antígeno B7-H1 , Leucemia Mieloide Aguda , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Línea Celular Tumoral , Receptor 2 Celular del Virus de la Hepatitis A , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Proteínas Nucleares/uso terapéutico , Receptor de Muerte Celular Programada 1 , Linfocitos T , Factores de Transcripción/uso terapéuticoRESUMEN
T-cell lymphoma (TCL) is an aggressive and genetically heterogeneous malignancy with adverse clinical outcomes; thus, it is worth exploring biomarkers for risk stratification. Previous studies have demonstrated that transmembrane protein 244 gene (TMEM244) is ectopically expressed in Sézary syndrome (SS). In this study, the expression level of TMEM244 and its prognostic value for TCL patients was explored by analyzing RNA-seq data of two large datasets (GSE132550 and GSE113113) containing 129 TCL patients and 13 healthy individuals (HIs) from the Gene Expression Omnibus (GEO) database, the PRJCA002270 dataset containing 124 patients with T-cell acute lymphoblastic leukemia (T-ALL) from the BioProject database, and peripheral blood (PB) samples of 24 TCL and 29 T-ALL patients, as well as 11 normal CD3 + T-cells from our clinical center (JNU). The results suggested that TMEM244 was significantly up-regulated in TCL patients compared with normal CD3 + T-cells or T-ALL in the JNU, GSE132550 and GSE113113 datasets (P < 0.05). However, TMEM244 shows no expression in patients with T-ALL in the JNU-T-ALL and PRJCA002270 datasets. The receiver operating characteristic (ROC) curve analysis indicated that TMEM244 expression had a very high accuracy in diagnosing TCL compared with T-ALL (area under the curve (AUC): 99.4%; P < 0.001). Importantly, high TMEM244 expression was significantly associated with poor OS and shorter 5-year restricted mean survival time (RMST) in TCL patients, especially those treated with chemotherapy. In summary, TMEM244 is also expressed in other types of TCL besides SS, but not in T-ALL. High TMEM244 expression is associated with poor OS in TCL patients, which might be a novel biomarker for prognostic stratification in TCL patients and facilitate the design of novel therapies.
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The molecular mechanisms underlying cancer immune escape are a core topic in cancer immunology research. Cancer cells can escape T cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1, CD274) immune checkpoint. Studying the PD-L1 regulatory pattern of tumor cells will help elucidate the molecular mechanisms of tumor immune evasion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-L1 at the transcriptional, post-transcriptional, and post-translational levels and influence the anti-tumor immune response by regulating PD-L1. In this review, we focus on the regulation of PD-L1 in cancer cells and summarize the underlying mechanisms.
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The B-cell CLL/lymphoma 11B gene (BCL11B) plays a crucial role in T-cell development, but its role in T-cell malignancies is still unclear. To study its role in the development of T-cell neoplasms, we generated an inducible BCL11B knockout in a murine T cell leukemia/lymphoma model. Mice, bearing human oncogenes TAL BHLH Transcription Factor 1 (TAL1; SCL) or LIM Domain Only 1 (LMO1), responsible for T-cell acute lymphoblastic leukemia (T-ALL) development, were crossed with BCL11B floxed and with CRE-ER/lox mice. The mice with a single oncogene BCL11Bflox/floxCREtg/tgTAL1tg or BCL11Bflox/floxCREtg/tgLMO1tg were healthy, bred normally, and were used to maintain the mice in culture. When crossed with each other, >90% of the double transgenic mice BCL11Bflox/floxCREtg/tgTAL1tgLMO1tg, within 3 to 6 months after birth, spontaneously developed T-cell leukemia/lymphoma. Upon administration of synthetic estrogen (tamoxifen), which binds to the estrogen receptor and activates the Cre recombinase, the BCL11B gene was knocked out by excision of its fourth exon from the genome. The mouse model of inducible BCL11B knockout we generated can be used to study the role of this gene in cancer development and the potential therapeutic effect of BCL11B inhibition in T-cell leukemia and lymphoma.
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Leucemia de Células T , Factores de Transcripción , Animales , Modelos Animales de Enfermedad , Proteínas con Dominio LIM/genética , Leucemia de Células T/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas Nucleares/genética , Proteínas Represoras/genética , Proteína 1 de la Leucemia Linfocítica T Aguda/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin-proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin-proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1-, 3-, and 5-year OS rates for patients with T-cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T-cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T-cells via the NPL4-mediated ubiquitin-proteasome pathway and offer a potential therapeutic option for T-cell malignancies.