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Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells in vivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.
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Inmunoterapia Adoptiva , Leucemia Mieloide Aguda , Receptores Quiméricos de Antígenos , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/inmunología , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , AnimalesRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL.
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Artritis Reumatoide , Dioxigenasas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Proteínas Proto-Oncogénicas/metabolismo , Auranofina/farmacología , Auranofina/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Dioxigenasas/genética , Dioxigenasas/metabolismo , Oxigenasas de Función Mixta/genética , Transducción de Señal , Metilación de ADN , ADN/metabolismo , Muerte Celular , Artritis Reumatoide/genéticaRESUMEN
Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.
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Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.
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Aminoácidos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Línea Celular Tumoral , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASC/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Factor de Transcripción Activador 4/metabolismoRESUMEN
Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Fumaratos/farmacología , Fumaratos/metabolismo , Microambiente Tumoral , Neoplasias/metabolismo , Transducción de SeñalRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy derived from T cells. Numerous CAR T therapies have been successfully applied to treat hematologic malignancies in the clinic. Nevertheless, there remain several challenges to the extensive application of CAR T cell therapy in T cell malignancies, especially in T-ALL. The main reason for CAR T therapy limitations is that T-ALL cells and normal T cells share antigens, which improves the difficulty of sorting pure T cells, resulting in product contamination, and would lead to CAR T cell fratricide. Thus, we considered creating a CAR on T-ALL tumor cells (CAR T-ALL) to prevent fratricide and eliminate tumor cells. We found that T-ALL cells transduced with CAR would actually commit fratricide. However, CAR T-ALL could kill only tumor cells on T-ALL cell lines, and other types of tumor cells had no killing function after being transferred with CAR. Furthermore, we created CD99 CAR with expression controlled by the Tet-On system on Jurkat cells, which could avoid the fratricide of CAR T-ALL during proliferation, ensuring the controllability of the killing time and effect. Jurkat transduced with a CAR-targeting antigen, which was expressed on other cancer cells, could kill other cancer cell lines, demonstrating that T-ALL cells could be used as tool cells for cancer therapy. Our study supplied a new feasible treatment regimen for cancer treatment in the clinic.
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Protein-drug conjugates are emerging tools to combat cancers. Here, we adopted an indirect thiolation-and-conjugation method as a general strategy to prepare protein-drug conjugates. We found for the first time that this method led to the formation of nanometric conjugates, probably due to the formation of intermolecular disulfide bonds, which facilitated enhanced uptake by cancer cells. As a proof-of-concept application in cancer therapy, a nanometric albumin-doxorubicin prodrug conjugate (NanoAlb-proDOX) was prepared. The nanometric size promoted its uptake by cancer cells, and the prodrug characteristic defined its selective cytotoxicity toward cancer cells in vitro and reduced side effects in vivo. In multiple tumor xenograft models, nanometric NanoAlb-proDOX showed superior antitumor activity and synergy with immune checkpoint blockade, probably due to the synergistically enhanced tumor CD8+ T-cell infiltration and activation. Hence, the thiolation-and-conjugation strategy may serve as a generally applicable method for preparing drug conjugates, and the proof-of-concept nanometric albumin-doxorubicin conjugate may be a good choice for antitumor therapy with the ability to co-stimulate the efficacy of immune checkpoint blockade.
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T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.
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Currently commercialized CAR-T cell therapies targeting CD19 and BCMA show great efficacy to cure B cell malignancies. However, intravenous infusion of these CAR-T cells severely destroys both transformed and normal B cells in most tissues and organs, in particular lung, leading to a critical question that what the impact of normal B cell depletion on pulmonary diseases and lung cancer is. Herein, we find that B cell frequency is remarkably reduced in both smoking carcinogen-treated lung tissues and lung tumors, which is associated with advanced cancer progression and worse patient survival. B cell depletion by anti-CD20 antibody significantly accelerates the initiation and progression of lung tumors, which is mediated by repressed tumor infiltration of T cells and macrophage elimination of tumor cells. These findings unveil the overall antitumor activity of B cells in lung cancer, providing novel insights into both mechanisms underlying lung cancer pathogenesis and clinical prevention post CAR-T cell therapy.
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BACKGROUND: Long-term outcome is unfavourable for relapsed/refractory (r/r) lymphoma patients who are resistant to salvage chemotherapy, even after subsequent autologous stem-cell transplantation (ASCT). Although anti-CD30 chimeric antigen receptor (CAR30) T-cell therapy induces high response rates in these patients, the duration of response is relatively limited. METHODS: This open-label, single-center and single-arm pilot study investigated the safety and efficacy of ASCT in tandem with CAR30 T-cell infusion in r/r CD30+ lymphoma. The primary endpoint was safety and key secondary endpoint was overall response rate, overall survival, progression-free survival, and duration of response. RESULTS: Five classical Hodgkin lymphoma (cHL) patients and 1 anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) patient were enrolled. The median age was 24 years. No patient had prior ASCT. Three patients (50.0%) relapsed for ≥ 2 times and 3 patients (50.0%) had primary refractory diseases. All had a Deauville score of 4 or 5, and 5 patients (83.3%) had a stable or progressive disease (SD/PD) at enrollment. All patients received myeloablative chemotherapy and infused CD34-positive hematopoietic stem cells (HSCs) and CAR30 T cells in tandem, with a median dose of 3.9 × 106/kg and 7.6 × 106/kg, respectively. Five paitents presented with cytokine release syndrome (CRS), all of which were grade 1. No neurotoxicity was observed. All patients had successful HSCs engraftment and reached an objective response, including 5 (4 cHL and 1 ALCL, 83.3%) with a complete response (CR) and 1 with a partial response (PR). With a median follow-up of 20.4 (range, 12.1-34.4) months, all remained alive and maintained their responses. CONCLUSION: Our work demonstrates the combined administration of ASCT and CAR30 T-cell therapy is well-tolerate and highly effective in r/r cHL and ALCL, even in PET-positive or chemorefractory patients who are expected to have inferior outcome after ASCT, although further large-scaled validation in prospective clinical trial is warranted. Trial registration The trial was registered with the Chinese Clinical Trial Registry (ChiCTR, number ChiCTR2100053662).
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Although great progress has been achieved in cancer treatment in the past decades, lung cancer remains the leading cause of cancer death, which is partially caused by the fact that most lung cancers are diagnosed at advanced stages. To improve the sensitivity and specificity of lung cancer diagnosis, the underlying mechanisms of current diagnosis methods are in urgent need to be explored. Herein, we find that the expression of EpCAM, the widely used molecular marker for tumor cell characterization and isolation, is strongly upregulated in primary lung tumors, which is caused by both gene amplification and promoter hypomethylation. In contrast, EpCAM expression is severely repressed in metastatic lung tumors, which can be reversed by epigenetic drugs, DNMT inhibitor 5-aza-dC and HDAC inhibitor MS-275. Moreover, tumor-associated macrophages (TAMs) impede EpCAM expression probably through TGFß-induced EMT signaling. These findings unveil the dynamic expression patterns of EpCAM and differential roles of epigenetic modification in EpCAM expression in primary and metastatic lung tumors, providing novel insights into tumor cell isolation and lung cancer diagnosis.
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CAR T-cell therapy is well tolerated and effective in patients with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). However, even second- generation anti-CD30 CAR T-cells with CD28 (28z) costimulatory domains failed to achieve the desired rate of complete responses. In the present study, we developed second-generation (CD28z) and third-generation (CD28BBz) CAR T-cells targeting CD30 and investigated their efficacy in vitro and in vivo. Both of CD28z and CD28BBz anti-CD30 CAR T cells were similar regarding amplification, T cell subsets distribution, T cell activity, effector/memory and exhaustion. However, we found that the 28BBz anti-CD30 CAR T-cells persist long-term, specifically homing to the tumor and mediating powerful antitumor activity in tumor xenograft models. Subsequently, we also demonstrated that the third generation anti-CD30 CAR T-cells have miner side effects or potential risks of tumorigenesis. Thus, anti-CD30 CAR T-cells represent a safe and effective treatment for Hodgkin lymphoma.
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Enfermedad de Hodgkin , Linfoma Anaplásico de Células Grandes , Anticuerpos , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/terapia , Humanos , Inmunoterapia Adoptiva , Antígeno Ki-1 , Linfoma Anaplásico de Células Grandes/patología , Linfocitos T/patologíaRESUMEN
TP53 gene alteration confers inferior prognosis in refractory/relapse aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL). From September 2016 to September 2020, 257 r/r B-NHL patients were assessed for eligibility for two trials in our center, assessing anti-CD19 and anti-CD22 chimeric antigen receptor (CAR19/22) T-cell cocktail treatment alone or in combination with autologous stem cell transplantation (ASCT). TP53 alterations were screened in 123 enrolled patients and confirmed in 60. CAR19/22 T-cell administration resulted in best objective (ORR) and complete (CRR) response rate of 87.1% and 45.2% in patients with TP53 alterations, respectively. Following a median follow-up of 16.7 months, median progression-free survival (PFS) was 14.8 months, and 24-month overall survival (OS) was estimated at 56.3%. Comparable ORR, PFS, and OS were determined in individuals with or without TP53 alterations, and in individuals at different risk levels based on functional stratification of TP53 alterations. CAR19/22 T-cell treatment in combination with ASCT resulted in higher ORR, CRR, PFS, and OS, but reduced occurrence of severe CRS in this patient population, even in individuals showing stable or progressive disease before transplantation. The best ORR and CRR in patients with TP53 alterations were 92.9% and 82.1%, respectively. Following a median follow-up of 21.2 months, 24-month PFS and OS rates in patients with TP53 alterations were estimated at 77.5% and 89.3%, respectively. In multivariable analysis, this combination strategy predicted improved OS. In conclusion, CAR19/22 T-cell therapy is efficacious in r/r aggressive B-NHL with TP53 alterations. Combining CAR-T cell administration with ASCT further improves long-term outcome of these patients.
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Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Linfoma de Células B , Receptores Quiméricos de Antígenos , Humanos , Linfoma de Células B/genética , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos/genética , Linfocitos T , Trasplante Autólogo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. The genomic mutation landscape of this Chinese cohort is very similar to the Western cohort published previously, except that the rate of NOTCH1 mutations is significant lower in the Chinese T-ALL patients. Among 47 recurrently mutated genes in 7 functional categories, we identify RAS pathway and PTEN mutations as poor survival factors for non-TAL and TAL subtypes, respectively. Mutations in the PI3K pathway are mutually exclusive with mutations in the RAS and NOTCH1 pathways as well as transcription factors. Further analysis demonstrates that approximately 43% of the high-risk patients harbor at least one potential actionable alteration identified in this study, and T-ALLs with RAS pathway mutations are hypersensitive to MEKi in vitro and in vivo. Thus, our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.
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Preservation and transportation are essential for the clinical application of chimeric antigen receptor T (CAR-T) cells. This study aimed to optimize a cryopreservation solution for CAR-T cells and evaluate the antitumor efficiency of CAR-T cells using this optimized solution in vitro and in vivo. First, the stability of the cryopreservation solution for CAR-T infusion was detected by the L27 (37) orthogonal experiment. Subsequently, osmolality and pH were analyzed for the preservation reagent. Additionally, apoptosis and CAR expression of CAR-T cells were measured by flow cytometry, and the cytotoxicity was determined by calcein-AM staining. The results showed that cryopreservation solutions used in this study demonstrated high chemical stability, which induced only 2% CAR-T cells apoptosis in optimal solutions, which were slightly lower than other commercial solutions. Moreover, the CAR expression was not significantly affected by preservation with these solutions. There were no significant differences in the cytotoxicity between fresh and thawed CAR-T cells cryopreserved in the cryopreservation solutions in vivo and in vitro. This study developed a new cryopreservation solution for CAR-T cells, and it was safe and also had negligible effects on the CAR-T cells antitumor activity.
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Receptores Quiméricos de Antígenos , Inmunoterapia Adoptiva/métodos , Linfocitos T , Criopreservación/métodosRESUMEN
The high-order chromatin structure, together with DNA methylation and other epigenetic marks, plays a vital role in gene regulation and displays abnormal status in cancer cells. Theoretical analyses are expected to provide a more unified understanding of the multi-omics data on the large variety of samples, and hopefully a common picture of carcinogenesis. In particular, we are interested in the question of whether an underlying origin DNA sequence exists for these epigenetic alterations. The human genome consists of two types of megabase-sized domain based on the distribution of CpG islands (CGIs) that show distinct structural, epigenetic, and transcriptional properties: CGI-rich and CGI-poor domains. Through an integrated analysis of chromatin structure, DNA methylation, and RNA sequencing data, we found that, in carcinogenesis, the two different types of domain display different structural changes and have an increased number of DNA methylation differences and transcriptional-level differences, compared with in noncancer cells. We also compared the structural features among carcinogenesis, senescence, and mitosis, showing the possible connection between chromatin structure and cell state, which could affect vital cancer-related properties. In summary, chromatin structure, DNA methylation, and gene expression, as well as their changes observed in several types of cancers, show a dependence on multiscale DNA sequence heterogeneity.
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Cromatina , Metilación de ADN , Carcinogénesis/genética , Cromatina/genética , Islas de CpG/genética , Metilación de ADN/genética , Genoma Humano , HumanosRESUMEN
CAR T cell therapy has shown dramatic clinical success in relapsed or refractory B-ALL and other hematological malignancies. However, the loss of specific antigens, cell fratricide, T cell aplasia, and normal T cell separation are challenges in treating T cell leukemia/lymphoma with CAR T therapy. CD99 is a promising antigen to target T-ALL and AML as it is strongly expressed on the majority of T-ALL and AML. Here, we isolated a low-affinity CD99 (12E7) antibody, which specifically recognizes leukemia cells over normal blood cells. Moreover, T cells transduced with an anti-CD99-specific CAR that contained the 12E7 scFv expanded with minor fratricide and without normal blood cells toxicity. We observed that our anti-CD99 CAR T cells showed robust cytotoxicity specifically against CD99+ T-ALL cell lines and primary tumor cells in vitro and significantly prolonged cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) models survival in vivo. Together, our results demonstrate that anti-CD99 CAR T cells could specifically recognize and efficiently eliminate CD99+ leukemia cells.
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Antígeno 12E7/inmunología , Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Receptores Quiméricos de Antígenos/uso terapéutico , Antígeno 12E7/antagonistas & inhibidores , Animales , Células Sanguíneas/efectos de los fármacos , Línea Celular Tumoral , Humanos , Inmunoterapia Adoptiva/efectos adversos , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.
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Cromosomas/metabolismo , Proteínas de Homeodominio/genética , Leucemia-Linfoma de Células T del Adulto/genética , Conformación Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linfocitos T/metabolismo , Translocación Genética , Acetilación , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Linaje de la Célula , Niño , Secuenciación de Inmunoprecipitación de Cromatina , Cromosomas/genética , Progresión de la Enfermedad , Elementos de Facilitación Genéticos , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica/genética , Regulación Leucémica de la Expresión Génica/inmunología , Ontología de Genes , Hematopoyesis/genética , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Inmunofenotipificación , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Pronóstico , Linfocitos T/patología , Adulto JovenRESUMEN
BACKGROUND: Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. METHODS: We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (n = 56) and validation (n = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort. RESULTS: In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC = 0.78), was superior to existing clinical indicators, such as LDH and stage. CONCLUSIONS: Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients.
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5-Metilcitosina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Ácidos Nucleicos Libres de Células/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , 5-Metilcitosina/sangre , 5-Metilcitosina/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores Farmacológicos/metabolismo , Estudios de Cohortes , Ciclofosfamida/metabolismo , Ciclofosfamida/uso terapéutico , Desmetilación del ADN/efectos de los fármacos , Doxorrubicina/metabolismo , Doxorrubicina/uso terapéutico , Femenino , Humanos , Modelos Logísticos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prednisona/metabolismo , Prednisona/uso terapéutico , Rituximab/metabolismo , Rituximab/uso terapéutico , Sensibilidad y Especificidad , Vincristina/metabolismo , Vincristina/uso terapéuticoRESUMEN
Background: The symptoms of coronavirus disease 2019 (COVID-19) range from moderate to critical conditions, leading to death in some patients, and the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited. Methods: We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5-hydroxymethylcytosine (5hmC) profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and develop a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 patients with severe COVID-19, and 38 patients with critical COVID-19. Results: Our warning model demonstrated that an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95% CI 0.77-0.85) and for severe patients developed into critical status was 0.92 (95% CI 0.89-0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95% CI 0.84-0.95). Conclusion: This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in patients with COVID-19. Our results show that phosphodiesterase 4D and ten-eleven translocation 2 may be important markers in the progression of COVID-19 disease.