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INTRODUCTION: Identifying patients with high-risk T-cell acute lymphoblastic leukemia (T-ALL) is crucial for personalized therapy; however, the lack of robust biomarkers hinders prognosis assessment. To address this issue, our study aimed to screen and validate genes whose expression may serve as predictive indicators of outcomes in T-ALL patients while also investigating the underlying molecular mechanisms. METHODS: Differentially expressed genes (DEGs) between T-ALL patients and healthy controls were identified by integrating data from three independent public datasets. Functional annotation of these DEGs and protein-protein interactions were also conducted. Further, we enrolled a prospective cohort of T-ALL patients (n = 20) at our center, conducting RNA-seq analysis on their bone marrow samples. Survival-based univariate Cox analysis was employed to identify gene expressions related to survival, and an intersection algorithm was sequentially applied. Furthermore, we validated the identified genes using cases from the Therapeutically Applicable Research to Generate Effective Treatments database, plotting Kaplan-Meier curves for secondary validation. RESULTS: Through the integration of survival-related genes with DEGs identified in T-ALL, our analysis revealed six T-ALL-specific genes, the expression levels of which were linked to prognostic value. Notably, the independent prognostic value of SLC40A1 and TES expression levels was confirmed in both an external cohort and a prospective cohort at our center. CONCLUSION: In summary, our preliminary study indicates that the expression levels of TES and SLC40A1 genes show promise as potential indicators for predicting survival outcomes in T-ALL patients.
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Introduction: Exploring monocytes' roles within the tumor microenvironment is crucial for crafting targeted cancer treatments. Methods: This study unveils a novel methodology utilizing four 20-color flow cytometry panels for comprehensive peripheral immune system phenotyping, specifically targeting classical, intermediate, and non-classical monocyte subsets. Results: By applying advanced dimensionality reduction techniques like t-distributed stochastic neighbor embedding (tSNE) and FlowSom analysis, we performed an extensive profiling of monocytes, assessing 50 unique cell surface markers related to a wide range of immunological functions, including activation, differentiation, and immune checkpoint regulation. Discussion: This in-depth approach significantly refines the identification of monocyte subsets, directly supporting the development of personalized immunotherapies and enhancing diagnostic precision. Our pioneering panel for monocyte phenotyping marks a substantial leap in understanding monocyte biology, with profound implications for the accuracy of disease diagnostics and the success of checkpoint-inhibitor therapies. Key findings include revealing distinct marker expression patterns linked to tumor progression and providing new avenues for targeted therapeutic interventions.
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Biomarcadores , Citometria de Fluxo , Imunofenotipagem , Monócitos , Humanos , Monócitos/imunologia , Monócitos/metabolismo , Citometria de Fluxo/métodos , Análise por Conglomerados , Imunofenotipagem/métodos , Microambiente Tumoral/imunologia , Neoplasias/imunologia , Neoplasias/diagnósticoRESUMO
Chronic myelomonocytic leukemia (CMML) treatment remains a pressing clinical challenge. We conducted a retrospective analysis on 52 CMML cases, exploring the effectiveness of combining venetoclax (Vene) with hypomethylating agents (HMAs). The study's findings show promise: the HMAs plus Vene group (n = 13, 53.8%) demonstrated superior overall response rates compared to the HMA monotherapy (mono) group (n = 19, 31.6%) and HMA plus arsenic trioxide group (n = 9, 22.2%) by the second cycle, and notably higher response rates (53.8% vs. 15.7%, p = 0.04) compared to the HMA mono group after four cycles. Over a median follow-up of 14.7 months, the HMAs plus Vene group exhibited significantly lower cumulative mortality (23.1%) compared to the other two groups (p = 0.003 and p = 0.008, respectively). Furthermore, this group displayed extended overall survival compared to the others. The study also delved into the molecular mechanisms, revealing significant BCL2 mRNA overexpression in patients with CMML. These findings suggest the potential for HMAs combined with Vene therapy in CMML but emphasize the necessity for further prospective studies to determine its precise role in managing CMML.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mielomonocítica Crônica , Sulfonamidas , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Leucemia Mielomonocítica Crônica/tratamento farmacológicoRESUMO
This study delves into the emerging role of ferroptosis in Myelodysplastic Neoplasms (MDS) and aims to identify a prognostic ferroptosis-related gene signature for MDS. Utilizing RNA-seq data and clinical information from the Gene Expression Omnibus database, the researchers extracted ferroptosis-related genes from the FerrDb website and conducted differential expression analysis using the 'limma' package in R. Hub ferroptosis-related genes in MDS were screened using the "RandomForest" and "carat" R packages. Kaplan -Meier and Cox regression analyses were employed to assess the prognostic role of three identified hub genes (BNIP3, MDM2, and RRM2). Receiver operator characteristic curve analysis confirmed the diagnostic efficacy of these genes. The study delved further into immune infiltration correlations, ncRNA-transcription factor coregulatory network analysis, and the identification of potential therapeutic drugs targeting hub ferroptosis-related genes in MDS. The researchers constructed a 3-gene signature-based risk score using datasets GSE58831 and GSE19429, demonstrating high accuracy (AUC > 0.75) in both datasets for survival prediction in MDS. A nomogram analysis reinforced the prognostic value of the risk-scoring model. Immunological analysis revealed an association between the risk score and immune infiltration. Quantitative reverse transcription polymerase chain reaction (qPCR) data indicated significant expression differences in MDM2, RRM2, and BNIP3 between MDS and healthy bone marrow samples. Notably, MDM2 and RRM2 showed decreased expression, while BNIP3 exhibited increased expression in MDS samples. This comprehensive study concludes that BNIP3, MDM2, and RRM2 hold diagnostic and prognostic significance in MDS and provide valuable insights into immune cell landscapes and potential therapeutic avenues for this condition.
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Ferroptose , Síndromes Mielodisplásicas , Neoplasias , Humanos , Prognóstico , Ferroptose/genética , Nomogramas , Bases de Dados Factuais , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genéticaRESUMO
BACKGROUND: Myofibroblasts (MFB), one of the major effectors of pathologic fibrosis, mainly derived from the activation of fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, for instance, idiopathic pulmonary fibrosis (IPF) and post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During the past decade, several methods were reported to block or reverse MFB differentiation, among which mesenchymal stem cells (MSC) have demonstrated potential but undetermined therapeutic values. However, the MSC-mediated regulation of FMT and underlying mechanisms remained largely undefined. METHOD: By identifying TGF-ß1 hypertension as the pivotal landmark during the pro-fibrotic FMT, TGF-ß1-induced MFB and MSC co-culture models were established and utilized to investigate regulations by MSC on FMT in vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR and flow cytometry were used. RESULT: Our data revealed that TGF-ß1 readily induced invasive signatures identified in fibrotic tissues and initiated MFB differentiation in normal FB. MSC reversibly de-differentiated MFB into a group of FB-like cells by selectively inhibiting the TGF-ß-SMAD2/3 signaling. Importantly, these proliferation-boosted FB-like cells remained sensitive to TGF-ß1 and could be re-induced into MFB. CONCLUSION: Our findings highlighted the reversibility of MSC-mediated de-differentiation of MFB through TGF-ß-SMAD2/3 signaling, which may explain MSC's inconsistent clinical efficacies in treating BO and other fibrotic diseases. These de-differentiated FB-like cells are still sensitive to TGF-ß1 and may further deteriorate MFB phenotypes unless the pro-fibrotic microenvironment is corrected.
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Células-Tronco Mesenquimais , Miofibroblastos , Humanos , Diferenciação Celular , Fibroblastos/metabolismo , Fibrose , Células-Tronco Mesenquimais/metabolismo , Miofibroblastos/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Proteína Smad3/metabolismoRESUMO
BACKGROUND: Chronic graft-versus-host disease (cGVHD) is the most common cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD4+ follicular helper T (Tfh) cells, specialized providers of T cell help to B cells, play a vital role in GVHD pathogenesis. B-cell lymphoma-6 (Bcl-6) transcription factor has been shown to be required for Tfh-mediated germinal center reactions. In this study, we would like to evaluate the effect of Bcl-6 on Tfh function in sclerodermatous cGVHD and the efficacy of Bcl-6 inhibitors (Bcl-6i) for treating a minor histocompatibility complex (miHC) mismatch model of sclerodermatous cGVHD (scl-cGVHD). METHODS: A minor histocompatibility haploidentical model of scl-cGVHD was established and received intraperitoneal injection of 79-6, a small-molecule inhibitor of Bcl-6. The clinical manifestations and survival times of cGVHD mice were recorded. The histological assessment was performed by hematoxylin-eosin (HE) and Masson's trichrome staining on the skin and lung tissues. Tfh cells and germinal center B cells in the spleen and peripheral blood were detected by flow cytometry. The cellular markers were immunostained in different organs. ELISA was performed to detect cytokine secretion. RESULTS: Bcl-6 inhibition by 79-6 improved the clinical manifestation of scl-cGVHD mice and prolonged their survival. The histopathologic damage, particular the fibrotic changes of scl-cGVHD mice was significantly relieved after 79-6 treatment. Furthermore, 79-6 treatment not only suppressed the development and function of Tfh and Tph cells in the peripheral blood, but also reduced the survival of Tfh cells in the spleen. Moreover, 79-6 decreased the frequency of GC plasmocytes accompanied by a reduction in IL-21. CONCLUSIONS: Our study demonstrates that Bcl-6 inhibitor could prevent murine sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation and suppressing the function of GC B cells, indicating that Bcl-6 inhibition may be a potential treatment for patients with cGVHD.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Camundongos , Animais , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Doença CrônicaRESUMO
Identifying subgroups of T-cell acute lymphoblastic leukemia (T-ALL) with poor survival will significantly influence patient treatment options and improve patient survival expectations. Current efforts to predict T-ALL survival expectations in multiple patient cohorts are lacking. A deep learning (DL)-based model was developed to determine the prognostic staging of T-ALL patients. We used transcriptome sequencing data from TARGET to build a DL-based survival model using 265 T-ALL patients. We found that patients could be divided into two subgroups (K0 and K1) with significant difference (P< 0.0001) in survival rate. The more malignant subgroup was significantly associated with some tumor-related signaling pathways, such as PI3K-Akt, cGMP-PKG and TGF-beta signaling pathway. DL-based model showed good performance in a cohort of patients from our clinical center (P = 0.0248). T-ALL patients survival was successfully predicted using a DL-based model, and we hope to apply it to clinical practice in the future.
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Hypomethylating agents (HMAs) are widely used in patients with higher-risk MDS not eligible for stem cell transplantation. However, the general response rate by HMAs is lesser than 50% in MDS patients, while the relapse rate is high. Emerging evidence indicates that demethylating effects committed by HMAs may facilitate the up-regulation of a range of immune checkpoints or cancer suppressor genes in patients with MDS, among which the programmed death protein 1 (PD-1) and its ligands are demonstrated to be prominent and may contribute to treatment failure and early relapse. Although results from preliminary studies with a limited number of enrolled patients indicate that combined administration of PD-1 inhibitor may yield extra therapeutic benefit in some MDS patients, identifications of this subgroup of patients and optimal timing for the anti-PD-1 intervention remain significant challenges. Dynamics of immune checkpoints and associated predictive values during HMA-treatment cycles remained poorly investigated. In this present study, expression levels of immune checkpoints PD-1 and its ligands PD-L1 and PD-L2 were retrospectively analyzed by quantitative PCR (Q-PCR) in a total of 135 myelodysplastic syndromes (MDS) cohort with higher-risk stratification. The prognostic value of dynamics of these immune checkpoints during HMA cycles was validated in two independent prospective cohorts in our center (NCT01599325 and NCT01751867). Our data revealed that PD-1 expression was significantly higher than that in younger MDS patients (age ≤ 60) and MDS with lower IPSS risk stratification (intermediate risk-1). A significantly up-regulated expression of PD-1 was seen during the first four HMA treatment cycles in MDS patients, while similar observation was not seen concerning the expression of PD-L1 or PD-L2. By utilizing binary logistic regression and receiver operating characteristic (ROC) models, we further identified that higher or equal to 75.9 PD-1 expressions after 2 cycles of HMA treatment is an independent negative prognostic factor in predicting acute myeloid leukemia (AML) transformation and survival. Collectively, our data provide rationales for monitoring the expression of PD-1 during HMA treatment cycles, a higher than 75.9 PD-1 expression may identify patients who will potentially benefit from the combined therapy of HMA and PD-1 inhibitors.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Antígeno B7-H1/genética , Estudos Clínicos como Assunto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Although chimeric antigen receptor (CAR)-modified adoptive T cell therapy is a promising immunotherapy for hematological malignancies, the efficacy improvement in relapsed/refractory acute lymphoblastic leukemia (ALL) with extramedullary infiltration and in multiple myeloma (MM) is still warranted. Since C3aR activation can promote the expansion of tumor-killing Th17 cells, we hypothesized that incorporating C3aR as a costimulatory domain would augment the antitumor activity of CAR-T. In this study, we introduced the C3aR domain into a CAR and generated BB-ζ-C3aR CAR-T targeting CD19 or BCMA. These new CAR-T exhibited a potent cytolytic ability to eradicate tumor cells expressing CD19 or BCMA in vitro. When administered intravenously to ALL or MM xenograft mouse models, BB-ζ-C3aR CAR-T reduced the tumor burden and improved the survival rate. Of note, these CAR-T could effectively eradicate subcutaneous CD19+ tumor cells, highlighting the therapeutic potential in extramedullary leukemia. Mechanistically, BB-ζ-C3aR CAR-T tended to exhibit a Th17 phenotype favoring tumor killing and suppressed Tregs. In addition, the induction of memory T cell in the BB-ζ-C3aR CAR-T cells indicated their long-term effects. Together, our findings suggest that the application of C3aR costimulation boosts the ability of CAR-T to eradicate aggressive tumor cells via Th17 expansion and memory T cell induction.
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Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Animais , Antígenos CD19 , Antígeno de Maturação de Linfócitos B , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva , Células T de Memória , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Células Th17RESUMO
Our group has reported previously on the role of various members of the protein arginine methyltransferase (PRMT) family, which are involved in epigenetic regulation, in the progression of leukemia. Here, we explored the role of PRMT7, given its unique function within the PRMT family, in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Genetic loss of Prmt7, and the development and testing of a small-molecule specific inhibitor of PRMT7, showed that targeting PRMT7 delayed leukemia development and impaired self-renewal of LSCs in a CML mouse model and in primary CML CD34+ cells from humans without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 resulted in reduced expressions of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to LSCs. These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Animais , Epigênese Genética , Glicina/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/uso terapêuticoRESUMO
OBJECTIVE: To establish the in vivo traceable acute myeloid leukemia mice model with Luciferase-Expressing KG1a Cells. METHODS: KG1a cells with stable luciferase gene expression (called as KG1a-Luc cells) were constructed by lentivirus transfection, then sifted out by puromycin. Eighteen male NOD-SCID-IL2rg-/-mice aged 8 to 12 weeks were randomly and equally divided into two groups: the control group and the KG1a-Luc group. The mice in KG1a-Luc group were injected with 200 µl PBS containing 5×106 KG1a-Luc cells through tail veins, and the mice in control group were injected with 200 µl PBS only. The bioluminescence imaging technology was used to monitor the tumor burden in vivo. The peripheral blood of the mice in both groups was analyzed by flow cytometry. After the mice were sacrificed, there were pathologic evaluations: bone marrow and spleens made into smears, and livers sliced to get paraffin sections. The survival time of the mice in the two groups was recorded and compared. RESULTS: KG1a cells expressing luciferase stably were successfully obtained. The tumor luminescence wildly spread at day 17 captured by in vivo imaging. The KG1a-Luc tumor cells could be detected in the peripheral blood of the mice, with the average percentage of (16.27±6.66)%. The morphology and pathology result showed that KG1a-Luc cells infiltrate was detected in bone marrow, spleens and livers. The survival time of the KG1a-Luc mice was notably shorter as compared with those in the control group, the median survival time was 30.5 days (95%CI: 0.008-0.260). CONCLUSION: The acute myeloid leukemia NOD-SCID-IL2rg-/-mouse model was successfully established by tail vein injection of 5×106 KG1a-Luc cells.
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Leucemia Mieloide Aguda , Animais , Modelos Animais de Doenças , Subunidade gama Comum de Receptores de Interleucina , Luciferases/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
Relapse of patients with chronic myelogenous leukemia (CML) may occur at least partially because leukemia stem cells (LSCs) lack sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib. The precise regulation of LSC stemness is incompletely understood. Given that traits of LSCs are subject to epigenetic regulation, we hypothesized that LSCs might be dependent on continuous active transcription of genes associated with super-enhancers (SEs), which might, in turn, suggest an opportunity for intervention. In this study, we tested this hypothesis and delineated the SE landscape in LSCs from patients with CML. Disruption of the SE-associated gene transcription by THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, efficiently eradicated LSCs in retroviral BCR-ABLdriven CML mice while sparing normal hematopoietic stem cells. Furthermore, we found that X-box binding protein 1 (XBP1), a substrate of mRNA-splicing endonuclease IRE1α in the unfolded protein response pathway, was an SE-associated oncogene in LSCs. Knockdown of XBP1 reduced survival and self-renewal capacity in primary CML CD34+ cells and eradicated LSCs in CML mice. Selectively blocking generation of the spliced form of Xbp1 by hematopoietic cellspecific Ire1 conditional knockout suppressed the progression of CML and impaired the leukemogenesis of LSCs in CML mice. Overall, we identified an epigenetic transcriptional program in LSCs, adding to evidence for the theory of "oncogene addiction" and suggesting a potential targeting strategy for CML.
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Elementos Facilitadores Genéticos , Leucemia Mieloide Aguda , Proteína 1 de Ligação a X-Box/genética , Animais , Humanos , Camundongos , Ligação Proteica , Células-TroncoRESUMO
Sophisticated cross-talk between bone marrow mesenchymal stromal cells (BM MSCs) and haematopoietic/leukaemic stem cells in patients with myelodysplastic syndromes (MDS) and myeloid leukaemia have been emphasized in previous reports. However, mesenchymal elements in patients with chronic myelomonocytic leukaemia (CMML) were poorly investigated. By utilizing a parallel RNA-sequencing method, we investigated the transcriptional profile and functional defects of primary BM MSCs from patients with CMML for the first time. Within a 24-patient cohort, transcriptional and functional analysis reveals a prominent enrichment of WNT/ß-catenin signalling and multiple biology processes. Deregulated expression of WNT/ß-catnin factors CTNNB1, CMYC, LEF1, and FRZB is associated with impaired proliferation, senescence phenotype, and abnormal secretion in CMML MSCs. The impaired ability to support healthy CD34+ haematopoietic stem and progenitor cells (HSPCs) correlates with activation of WNT/ß-catenin signalling in CMML MSCs. Furthermore, we observed an association between WNT/ß-catenin factors and treatment response to hypomethylating agents (HMAs) in a cohort of patients with MDS/myeloproliferative neoplasms (MPNs). Taken together, our study provides evidence for transcriptional and functional abnormalities in CMML MSCs, and suggests potential prognostic value of evaluating WNT/ß-catenin signalling in patients with CMML.
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Células da Medula Óssea/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Células-Tronco Mesenquimais/metabolismo , Proteínas de Neoplasias , RNA-Seq , Via de Sinalização Wnt/genética , Adulto , Idoso , Feminino , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genéticaRESUMO
The application of tyrosine kinase inhibitors (TKIs) in clinic has revolutionized chronic myelogenous leukemia (CML) treatment, but fails to eliminate leukemia stem cells (LSCs), which are considered as roots of drug resistance and disease relapse. Thus, eradication of LSCs may be a promising strategy for curing CML. In this study, we found that protein lysine methyltransferase G9A was overexpressed in CML LSCs. The upregulation of G9A by BCR-ABL was independent on its tyrosine kinase activity. Knockdown of G9A by shRNAs or pharmacological inhibition of G9A by UNC0642 significantly suppressed survival and impaired self-renewal capacity of CML LSCs. Inhibition of G9a eradicated LSCs in CML mice driven by BCR-ABL gene and dramatically prolonged survival of the mice. Ex vivo treatment with G9A inhibitor inhibited long-term engraftment of CML CD34+ cells in immunodeficient mice. Mechanically, tumor suppressor SOX6 was identified as a direct target of G9A in CML LSCs by RNA-seq analysis. Silencing Sox6 at least partially rescued G9a knockdown-mediated LSCs elimination in vivo. Our findings improve the understanding of LSC regulation network and validate G9A as a therapeutic target in CML LSCs. Targeting G9A may be considered as an additional strategy for the treatment of patients with CML.
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Proteínas de Fusão bcr-abl/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Quinazolinas/farmacologia , Fatores de Transcrição SOXD/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Fatores de Transcrição SOXD/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: AML is a heterogeneous disease both in genomic and proteomic backgrounds, and variable outcomes may appear in the same cytogenetic risk group. Therefore, it is still necessary to identify new antigens that contribute to diagnostic information and to refine the current risk stratification. METHODS: The expression of C-type lectin-like molecule-1 (CLL-1) in AML blasts was examined in 52 patients with newly diagnosed or relapsed/refractory AML and was compared with two other classic markers CD33 and CD34 in AML, in order to assess the value of CLL-1 as an independent biomarker or in combination with other markers for diagnosis in AML. Subsequently, the value of CLL-1 as a biomarker for prognosis was assessed in this malignant tumor. RESULTS: The results showed that CLL-1 was expressed on the cell surface of the majority of AML blasts (78.8%) and also expressed on leukemic stem cells in varying degree but absent on normal hematopoietic stem cells. Notably, CLL-1 was able to complement the classic markers CD33 or CD34. After dividing the cases into CLL-1high and CLL-1low groups according to cutoff 59.0%, we discovered that event-free survival and overall survival (OS) of the CLL-1low group were significantly lower than that of the CLL-1high group, and low CLL-1 expression seems to be independently associated with shorter OS. CONCLUSIONS: These preliminary observations identified CLL-1 as a biomarker for diagnosis and prognosis of AML.
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Biomarcadores Tumorais/sangue , Regulação Leucêmica da Expressão Gênica , Lectinas Tipo C/sangue , Leucemia Mieloide Aguda , Proteínas de Neoplasias/sangue , Receptores Mitogênicos/sangue , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Inteligência Artificial , COVID-19/terapia , Sistemas CRISPR-Cas , Diferenciação Celular , Movimento Celular , Ensaios Clínicos como Assunto , Vesículas Extracelulares/genética , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/transplante , Engenharia Genética/métodos , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismoRESUMO
Background: Emerging evidence has proven that ferroptosis plays an important role in the development of acute myeloid leukemia (AML), whereas the exact role of ferroptosis-associated genes in AML patients' prognosis remained unclear. Materials and Methods: Gene expression profiles and corresponding clinical information of AML cases were obtained from the TCGA (TCGA-LAML), GEO (GSE71014), and TARGET databases (TARGET-AML). Patients in the TCGA cohort were well-grouped into two clusters based on ferroptosis-related genes, and differentially expressed genes were screened between the two clusters. Univariate Cox and LASSO regression analyses were applied to select prognosis-related genes for the construction of a prognostic risk-scoring model. Survival analysis was analyzed by Kaplan-Meier and receiver operator characteristic curves. Furthermore, we explored the correlation of the prognostic risk-scoring model with immune infiltration and chemotherapy response. Risk gene expression level was detected by quantitative reverse transcription polymerase chain reaction. Results: Eighteen signature genes, including ZSCAN4, ASTN1, CCL23, DLL3, EFNB3, FAM155B, FOXL1, HMX2, HRASLS, LGALS1, LHX6, MXRA5, PCDHB12, PRINS, TMEM56, TWIST1, ZFPM2, and ZNF560, were developed to construct a prognostic risk-scoring model. AML patients could be grouped into high- and low-risk groups, and low-risk patients showed better survival than high-risk patients. Area under the curve values of 1, 3, and 5 years were 0.81, 0.827, and 0.786 in the training set, respectively, indicating a good predictive efficacy. In addition, age and risk score were the independent prognostic factors after univariate and multivariate Cox regression analyses. A nomogram containing clinical factors and prognostic risk-scoring model was constructed to better estimate individual survival. Further analyses demonstrated that risk score was associated with the immune infiltration and response to chemotherapy. Our experiment data revealed that LGALS1 and TMEM56 showed notably decreased expression in AML samples than that of the normal samples. Conclusion: Our study shows that the prognostic risk-scoring model and key risk gene may provide potential prognostic biomarkers and therapeutic option for AML patients.
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Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.
Assuntos
Interleucina-6/imunologia , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células HEK293 , Humanos , Ativação Linfocitária/imunologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosAssuntos
Vírus da Hepatite B , Hepatite B/complicações , Hepatite B/virologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Modelos Animais de Doenças , Feminino , Hepatite B/diagnóstico , Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Camundongos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To illustrate the potential effects and mechanism of extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) on fibrosis in sclerodermatous chronic graft-versus-host-disease (cGVHD) models after allogeneic hematopoietic stem cell transplantation. METHODS: We first observed the therapeutic effects of MSC-EVs on a minor histocompatibility haploidentical model of sclerodermatous cGVHD and the function of MSC-EVs on skin fibrosis and macrophage activation and the related pro-fibrosis protein. Additionally, we observed the effects of MSC-EVs on B cells, the T follicular helper cell (TFH) and germinal center B cell (GC B cells) interaction and the ratio of B cell activation factor (BAFF) to B cells in vivo. RESULTS: MSC-EVs treatment could alleviate the cGVHD scores and fibrosis of skin in sclerodermatous cGVHD mice, and this was associated with a reduction macrophage percentage in the skin and spleen, and a reduction in macrophage infiltration and TGF-ß and smad2 production in the skin. Additionally, MSC-EVs influence B cells immune response by blocking the TFH/GC B cells interaction and reducing the ratio of BAFF to B cells in vivo. CONCLUSION: MSC-EVs prevent the fibrosis of sclerodermatous cGVHD mouse model by suppressing the activation of macrophages and B cells immune response.