RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy arising from immature thymocytes. Unlike well-known oncogenic transcription factors, such as NOTCH1 and MYC, the involvement of chromatin remodeling factors in T-ALL pathogenesis is poorly understood. Here, we provide compelling evidence on how SWI/SNF chromatin remodeling complex contributes to human T-ALL pathogenesis. Integrative analysis of transcriptomic and ATAC-Seq datasets revealed high expression of SMARCA4, one of the subunits of the SWI/SNF complex, in T-ALL patient samples and cell lines compared to normal T cells. Loss of SMARCA protein function resulted in apoptosis induction and growth inhibition in multiple T-ALL cell lines. ATAC-Seq analysis revealed a massive reduction in chromatin accessibility across the genome after the loss of SMARCA protein function. RUNX1 interacts with SMARCA4 protein and co-occupies the same genomic regions. Importantly, the NOTCH1-MYC pathway was primarily affected when SMARCA protein function was impaired, implicating SWI/SNF as a novel therapeutic target.
Asunto(s)
Ensamble y Desensamble de Cromatina , ADN Helicasas , Proteínas Nucleares , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Factores de Transcripción , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Receptor Notch1/metabolismo , Receptor Notch1/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Apoptosis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Regulación Leucémica de la Expresión Génica , Línea Celular TumoralRESUMEN
It is crucial to quickly bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic reconstitution. Here we report on the efficacy and safety of donor CD7 chimeric antigen receptor (CAR) T cell therapy (CAR-T) bridging to allo-HSCT in treating 12 patients with relapsed/refractory (r/r) T-ALL or T-cell lymphoblastic lymphoma (T-LBL). The median time from CAR-T infusion to allo-HSCT was 33.5 days (range, 30 to 55 days). With reduced-intensity conditioning, all patients except 1 successfully engrafted. With a mean follow-up of 301 days (range, 238 to 351 days), the remaining 11 patients were alive and disease-free at their last follow-up. Acute graft-versus-host disease (GVHD) was observed in 3 patients, and chronic GVHD developed in 3 patients, all with a limited pattern. Under the current protocol, infection was the main complication post-transplantation, and all infections were well controlled except in 1 patient, who died of multiple organ failure caused by an infection-induced inflammatory cytokine storm at days 14 post-transplantation. One patient relapsed (CD7+), and 3 patients became minimal residual disease (MRD) positive (CD7+ in 1, CD7- in 1, fusion gene positive only in 1). Subsequently, all 3 of these patients achieved an MRD-negative complete remission with either CD7 CAR-T reinfusion or immunosuppressive agent withdrawal. Our study shows for the first time that a novel strategy of donor CD7 CAR-T bridging to allo-HSCT can be highly effective and feasible in improving disease-free survival for patients with r/r T-ALL or T-LBL.
Asunto(s)
Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores Quiméricos de Antígenos , Humanos , Antígenos CD7 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/terapiaRESUMEN
Acute lymphoblastic leukaemia (ALL) is an aggressive haematological tumour driven by the malignant transformation and expansion of B-cell (B-ALL) or T-cell (T-ALL) progenitors. The evolution of T-ALL pathogenesis encompasses different master developmental pathways, including the main role played by Notch in cell fate choices during tissue differentiation. Recently, a growing body of evidence has highlighted epigenetic changes, particularly the altered expression of microRNAs (miRNAs), as a critical molecular mechanism to sustain T-ALL. The immune response is emerging as key factor in the complex multistep process of cancer but the role of miRNAs in anti-leukaemia response remains elusive. In this review we analyse the available literature on miRNAs as tuners of the immune response in T-ALL, focusing on their role in Natural Killer, T, T-regulatory and Myeloid-derived suppressor cells. A better understanding of this molecular crosstalk may provide the basis for the development of potential immunotherapeutic strategies in the leukemia field.
Asunto(s)
Biomarcadores de Tumor , Regulación Leucémica de la Expresión Génica , Inmunomodulación/genética , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Animales , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Interferencia de ARN , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Transcripción Genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Transglutaminase 2 (TGM2) is a Ca2+dependent enzyme that is closely associated with cancer progression; however, the function of TGM2 in Tcell lymphoma remains unclear. In the present study, TGM2 was identified as an upregulated gene by bioinformatics analysis of the microarray datasets GSE132550 and GSE143382 from the Gene Expression Omnibus database. The effects and mechanisms of TGM2 on Tcell lymphoma cells were evaluated using the Cell Counting Kit8, colony formation assay, 5ethynyl2'deoxyuridine (EdU) assay, flow cytometry, reverse transcriptionquantitative polymerase chain reaction, western blotting and gene set enrichment analysis (GSEA). TGM2 expression was shown to be elevated in formalinfixed paraffinembedded skin biopsies from patients with Tcell lymphoma relative to skin tissue from healthy cases. TGM2 expression was also increased in Tcell lymphoma cell lines compared with that in CD4+ T cells. Transfection with TGM2 small interfering RNAs (siRNAs) decreased the number of EdUpositive cells, and the viability and colony formation of Tcell lymphoma cells. Furthermore, TGM2 siRNAs enhanced the apoptosis of Tcell lymphoma cells potentially via cleavage of caspase3 and poly ADPribose polymerase. GSEA identified the IL6/JAK/STAT3 pathway as a potential downstream signalling pathway of TGM2. Notably, the effects of TGM2 siRNAs on Tcell lymphoma cells were attenuated by IL6 and accelerated by IL6/JAK/STAT3 inhibitor AG490. These findings indicated that TGM2 siRNAs inhibited the proliferation of Tcell lymphoma cells by regulating the IL6/JAK/STAT3 signalling pathway; therefore, TGM2 may function as a potential therapeutic target for Tcell lymphoma.
Asunto(s)
Interleucina-6/metabolismo , Quinasas Janus/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteína Glutamina Gamma Glutamiltransferasa 2/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Apoptosis/genética , Línea Celular Tumoral , Bases de Datos Genéticas , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Interferencia de ARNRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 inhibitor (tofacitinib) and a MDM2 inhibitor (idasanutlin) reduces the Phf6 KO and JAK3M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.
Asunto(s)
Transformación Celular Neoplásica/patología , Janus Quinasa 3/metabolismo , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Represoras/fisiología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Humanos , Janus Quinasa 3/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Despite marked advances in the clinical therapies, clinical outcome of most T-cell acute lymphoblastic leukemia (T-ALL) patients remains poor, due to the high risk of relapse, even after complete remission. Previous studies suggest that the NAD-dependent deacetylase sirtuin 1 (SIRT1) has a dual role in hematologic malignancies, acting as a tumor suppressor or tumor promoter depending on the tumor type. However, little is known about the expression and functions of SIRT1 in T-ALL leukemogenesis. METHODS: Public RNA-seq data, a Notch1 driven T-ALL mouse model and γ-secretase inhibitor were used to identify SIRT1 expression in T-ALL. We knocked down SIRT1 expression with ShRNAs and assessed the impacts of SIRT1 deficiency on cell proliferation, colony formation, the cell cycle and apoptosis. Transgenic SIRT1 knockout mice were used to determine the function of SIRT1 in vivo. RT-PCR, western blot, co-immunoprecipitation and ubiquitination analyses were used to detect SIRT1, p27 and CDK2 expression and their interactions. RESULTS: SIRT1 protein expression was positively correlated with the activation of Notch1. Downregulation of SIRT1 expression suppressed the proliferation and colony formation of T-ALL cell lines, which was reversed by SIRT1 overexpression. SIRT1 silencing prolonged the lifespan of T-ALL model mice. We demonstrated that p27 was involved in the downstream mechanism of cell cycle arrest induced by silencing SIRT1. SIRT1 increased the phosphorylation of p27 on Thr187 by deacetylating CDK2 and enhanced the interaction between p27 and SKP2 leading to the degradation of p27. CONCLUSION: Our findings suggest that SIRT1 is a promising target in T-ALL and offer a mechanistic link between the upregulation of SIRT1 and downregulation of p27.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Sirtuina 1/metabolismo , Acetilación , Animales , Biomarcadores de Tumor , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Genes myc , Humanos , Ratones , Ratones Noqueados , Fosforilación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor Notch1/metabolismo , Transducción de Señal , Sirtuina 1/genética , UbiquitinaciónRESUMEN
Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from NUP98-HOXD13 fusion (NHD13) transgenic mice frequently acquire somatic Idh mutations when they transform to acute myeloid leukemia, we generated Idh2R140Q/NHD13 double transgenic mice. Idh2R140Q/NHD13 transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. Idh2R140Q/NHD13 leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for Idh2R140Q/NHD13 DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including KRAS, PTPN11, JAK3, SH2B3, and EZH2 were also found in Idh2R140Q/NHD13 DN1/DN2 T-ALL. In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy. SIGNIFICANCE: T-cell leukemia induced in Idh2R140Q/NUP98-HOXD13 mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.
Asunto(s)
Proteínas de Homeodominio/metabolismo , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Timocitos/metabolismo , Animales , Biomarcadores de Tumor , Diferenciación Celular/genética , Línea Celular Tumoral , Biología Computacional/métodos , Metilación de ADN , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Xenoinjertos , Humanos , Inmunofenotipificación , Ratones , Ratones Transgénicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Timocitos/patología , TranscriptomaRESUMEN
The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al Calcio/metabolismo , Regulación Neoplásica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptores Notch/metabolismo , Bazo/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Notch/genética , Bazo/metabolismo , Bazo/cirugía , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Regulación Leucémica de la Expresión Génica , Factor de Transcripción Ikaros/fisiología , Proteínas con Dominio LIM/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismoRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL.
Asunto(s)
Respiración de la Célula/efectos de los fármacos , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxazoles/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Biomarcadores , Muerte Celular , Línea Celular Tumoral , Humanos , Leucocitos Mononucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologíaRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a highly malignant pediatric leukemia, where few therapeutic options are available for patients which relapse. We find that therapeutic targeting of GLI transcription factors by GANT-61 is particularly effective against NOTCH1 unmutated T-ALL cells. Investigation of the functional role of GLI1 disclosed that it contributes to T-ALL cell proliferation, survival, and dissemination through the modulation of AKT and CXCR4 signaling pathways. Decreased CXCR4 signaling following GLI1 inactivation was found to be prevalently due to post-transcriptional mechanisms including altered serine 339 CXCR4 phosphorylation and cortactin levels. We also identify a novel cross-talk between GLI transcription factors and FOXC1. Indeed, GLI factors can activate the expression of FOXC1 which is able to stabilize GLI1/2 protein levels through attenuation of their ubiquitination. Further, we find that prolonged GLI1 deficiency has a double-edged role in T-ALL progression favoring disease dissemination through the activation of a putative AKT/FOXC1/GLI2 axis. These findings have clinical significance as T-ALL patients with extensive central nervous system dissemination show low GLI1 transcript levels. Further, T-ALL patients having a GLI2-based Hedgehog activation signature are associated with poor survival. Together, these findings support a rationale for targeting the FOXC1/AKT axis to prevent GLI-dependent oncogenic Hedgehog signaling.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Transducción de Señal , Proteína con Dedos de Zinc GLI1/metabolismo , Animales , Apoptosis , Biopsia , Puntos de Control del Ciclo Celular , Biología Computacional/métodos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Proteínas Hedgehog/metabolismo , Humanos , Inmunohistoquímica , Ratones , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Pronóstico , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores CXCR4/metabolismo , Factores de TranscripciónRESUMEN
Childhood leukemia is cancer that seriously threatens the life of children in China. Poor sensitivity to chemotherapy and susceptibility to drug resistance are the reasons for the treatment of T-cell acute lymphocytic leukemia (T-ALL) being extremely difficult. Moreover, traditional intensive chemotherapy regimens cause great damage to children. Therefore, it is highly important to search for targeted drugs and develop a precise individualized treatment for child patients. There are activating mutations in the NOTCH1 gene in more than 50% of human T-ALLs and the Notch signaling pathway is involved in the pathogenesis of T-ALL. In this review, we summarize the progress in research on T-ALL and Notch1 signaling pathway inhibitors to provide a theoretical basis for the clinical treatment of T-ALL.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/fisiología , Transducción de Señal/fisiología , Niño , Humanos , Receptor Notch1/genéticaRESUMEN
The role of cortactin in T-cell acute lymphoblastic leukemia (T-ALL) tissue infiltration has been previously reported. However, its impact on patients' responsiveness to therapy and patient's outcome was not previously addressed. This study was conducted on 60 T-ALL pediatric patients at diagnosis and 10 nonleukemic controls. Cortactin and HS1 expressions were identified by real-time polymerase chain reaction. Cortactin and HS1 expression were significantly higher in T-All patients as compared with controls as well as postinduction levels (P≤0.001 for both). The high cortactin expression was significantly associated with high peripheral white cell counts (P≤0.001), blood blast cells (P≤0.001) and central nervous system (CNS) infiltration (P≤0.001), and early precursor T-ALL subtype (P≤0.001) as compared with the remaining groups. The induction of remission response was significantly higher in T-ALL patients with lower cortactin expression levels as compared with T-ALL patients with higher one (P≤0.001). The high cortactin and HS1 expressions were significantly predictors of CNS infiltrations (hazard ratios [HR]: 1.051, confidence interval [CI]: 1.02-1.13, P=0.04 and HR: 1.87, CI: 1.23-2.091, P=0.002, respectively) and bone marrow relapse (HR: 1.43, CI: 1.18-1.92, P=0.004 and HR: 1.07, CI: 1.01-1.24, P=0.002, respectively). Furthermore, high cortactin expression levels were associated with shorter B-ALL patients' overall survival as compared with those with lower cortactin levels (P=0.002). In conclusion, high expression of cortactin and/or HS1 at diagnosis is a bad prognostic marker of T-ALL patients' outcome. Moreover, cortactin and/or HS1 expression could be used as a biomarker for refining risk stratification of T-ALL.
Asunto(s)
Cortactina/genética , Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Pronóstico , Riesgo , Análisis de SupervivenciaRESUMEN
The Dlx5 homeobox gene was first implicated as an oncogene in a T-ALL mouse model expressing myristoylated (Myr) Akt2. Furthermore, overexpression of Dlx5 was sufficient to drive T-ALL in mice by directly activating Akt and Notch signaling. These findings implied that Akt2 cooperates with Dlx5 in T-cell lymphomagenesis. To test this hypothesis, Lck-Dlx5;Lck-MyrAkt2 transgenic mice were generated. MyrAkt2 synergized with Dlx5 to greatly accelerate and enhance the dissemination of T-lymphomagenesis. RNA-seq analysis performed on lymphomas from Lck-Dlx5;Lck-MyrAkt mice revealed upregulation of genes involved in the Wnt and cholesterol biosynthesis pathways. Combined RNA-seq and ChIP-seq analysis of lymphomas from Lck-Dlx5;Lck-MyrAkt mice demonstrated that ß-catenin directly regulates genes involved in sterol regulatory element binding transcription factor 2 (Srebf2)-cholesterol synthesis. These lymphoma cells had high Lef1 levels and were highly sensitive to ß-catenin and Srebf2-cholesterol synthesis inhibitors. Similarly, human T-ALL cell lines with activated NOTCH and AKT and elevated LEF1 levels were sensitive to inhibition of ß-catenin and cholesterol pathways. Furthermore, LEF1 expression positively correlated with expression of genes involved in the cholesterol synthesis pathway in primary human T-ALL specimens. Together, these data suggest that targeting ß-catenin and/or cholesterol biosynthesis, together with AKT, could have therapeutic efficacy in a subset of T-ALL patients.
Asunto(s)
Colesterol/biosíntesis , Proteínas de Homeodominio/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Linfocitos T/metabolismo , Vía de Señalización Wnt , Animales , Línea Celular Tumoral , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , beta Catenina/antagonistas & inhibidores , beta Catenina/metabolismoAsunto(s)
Crisis Blástica/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Adulto , Antígenos CD/análisis , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Crisis Blástica/etiología , Humanos , Hibridación Fluorescente in Situ , Masculino , Células Madre Neoplásicas/química , Células Madre Neoplásicas/patología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Espacio RetroperitonealRESUMEN
Despite harboring mutations in oncogenes and tumor suppressors that promote cancer growth, T-cell acute lymphoblastic leukemia (T-ALL) cells require exogenous cells or signals to survive in culture. We previously reported that myeloid cells, particularly dendritic cells, from the thymic tumor microenvironment support the survival and proliferation of primary mouse T-ALL cells in vitro. Thus, we hypothesized that tumor-associated myeloid cells would support T-ALL in vivo. Consistent with this possibility, in vivo depletion of myeloid cells results in a significant reduction in leukemia burden in multiple organs in 2 distinct mouse models of T-ALL and prolongs survival. The impact of the myeloid compartment on T-ALL growth is not dependent on suppression of antitumor T-cell responses. Instead, myeloid cells provide signals that directly support T-ALL cells. Transcriptional profiling, functional assays, and acute in vivo myeloid-depletion experiments identify activation of IGF1R as a critical component of myeloid-mediated T-ALL growth and survival. We identify several myeloid subsets that have the capacity to directly support survival of T-ALL cells. Consistent with mouse models, myeloid cells derived from human peripheral blood monocytes activate IGF1R and directly support survival of primary patient T-ALL cells in vitro. Furthermore, enriched macrophage gene signatures in published clinical samples correlate with inferior outcomes for pediatric T-ALL patients. Collectively, these data reveal that tumor-associated myeloid cells provide signals critical for T-ALL growth in multiple organs in vivo and implicate tumor-associated myeloid cells and associated signals as potential therapeutic targets.
Asunto(s)
Comunicación Celular , Células Mieloides/inmunología , Células Mieloides/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Microambiente Tumoral , Biomarcadores , Línea Celular Tumoral , Perfilación de la Expresión Génica , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transducción de SeñalAsunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , PronósticoRESUMEN
OPINION STATEMENT: T cell acute lymphoblastic leukemia (T-ALL) occurs in approximately 25-30% of adult ALL diagnoses. Historically, B cell ALL (B-ALL) and T-ALL have been treated in the same fashion despite differences in the biology of disease. Outcomes in the adolescent/young adult (AYA) population have improved significantly with the utilization of pediatric-based regimens. In addition, there may now be a role for the addition of nelarabine to frontline treatment in the AYA population. In older adults, choices in which regimen to pursue should account for the potential toxicities associated with pediatric-based regimens. Measurable residual disease (MRD) has taken on increasing prognostic value in T-ALL and may help to identify which patients should receive an allogeneic stem cell transplant. T cell lymphoblastic lymphoma (T-LBL) has traditionally been treated similarly to T-ALL, but additional management questions must be considered. Mediastinal irradiation does not seem to clearly improve outcomes, and there is considerable heterogeneity in the central nervous system (CNS) prophylaxis strategy used in prospective trials. CNS prophylaxis in AYA patients with T-ALL, on the other hand, can be safely achieved with intrathecal chemotherapy alone. Prospective data regarding CNS prophylaxis strategies in older adults are currently not available. Nelarabine-based regimens currently remain the standard in relapsed/refractory T-ALL; however, novel therapies targeting molecular aberrations in T-ALL are actively being investigated.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Adolescente , Adulto , Factores de Edad , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Resistencia a Medicamentos , Predisposición Genética a la Enfermedad , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Recurrencia , Retratamiento , Resultado del Tratamiento , Adulto JovenAsunto(s)
Terapia Genética/efectos adversos , Genómica , Neoplasias Primarias Secundarias/etiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Biomarcadores de Tumor , Perfilación de la Expresión Génica , Pruebas Genéticas , Terapia Genética/métodos , Genómica/métodos , Humanos , Inmunofenotipificación , Neoplasias Primarias Secundarias/diagnóstico , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Secuenciación del Exoma , Síndrome de Wiskott-Aldrich/complicaciones , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapiaRESUMEN
Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.