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1.
Mol Cancer ; 23(1): 114, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38811984

RESUMEN

BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1ß production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1ß and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1ß, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.


Asunto(s)
Progresión de la Enfermedad , Fosfohidrolasa PTEN , Neoplasias de la Próstata , Microambiente Tumoral , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Animales , Ratones , Humanos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Microambiente Tumoral/inmunología , Fenotipo Secretor Asociado a la Senescencia , Proteínas Proto-Oncogénicas c-jun/metabolismo , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Perfilación de la Expresión Génica , Senescencia Celular/genética , Modelos Animales de Enfermedad
2.
Blood ; 139(25): 3617-3629, 2022 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-35344582

RESUMEN

Genetic alterations in the DNA damage response (DDR) pathway are a frequent mechanism of resistance to chemoimmunotherapy (CIT) in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumor cells and macrophages. Here, we show that loss of multiple different members of the DDR pathway inhibits macrophage phagocytic capacity in vitro and in vivo. Particularly, loss of TP53 led to decreased phagocytic capacity ex vivo across multiple B-cell malignancies. We demonstrate via in vivo cyclophosphamide treatment using the Eµ-TCL1 mouse model that loss of macrophage phagocytic capacity in Tp53-deleted leukemia is driven by a significant downregulation of a phagocytic transcriptomic signature using small conditional RNA sequencing. By analyzing the tumor B-cell proteome, we identified a TP53-specific upregulation of proteins associated with extracellular vesicles (EVs). We abrogated EV biogenesis in tumor B-cells via clustered regularly interspaced short palindromic repeats (CRISPR)-knockout (KO) of RAB27A and confirmed that the EVs from TP53-deleted lymphoma cells were responsible for the reduced phagocytic capacity and the in vivo CIT resistance. Furthermore, we observed that TP53 loss led to an upregulation of both PD-L1 cell surface expression and secretion of EVs by lymphoma cells. Disruption of EV bound PD-L1 by anti-PD-L1 antibodies or PD-L1 CRISPR-KO improved macrophage phagocytic capacity and in vivo therapy response. Thus, we demonstrate enhanced EV release and increased PD-L1 expression in TP53-deficient B-cell lymphomas as novel mechanisms of macrophage function alteration in CIT resistance. This study indicates the use of checkpoint inhibition in the combination treatment of B-cell malignancies with TP53 loss.


Asunto(s)
Antígeno B7-H1 , Vesículas Extracelulares , Linfoma de Células B , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Vesículas Extracelulares/metabolismo , Linfoma/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Macrófagos/metabolismo , Ratones , Neoplasias/metabolismo
3.
Br J Haematol ; 202(5): 985-994, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37357529

RESUMEN

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Linfoma Anaplásico de Células Grandes , Niño , Humanos , Quinasa de Linfoma Anaplásico , Crizotinib/farmacología , Crizotinib/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/patología , Xenoinjertos , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico
4.
Blood ; 138(7): 544-556, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-33735912

RESUMEN

Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.


Asunto(s)
Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Movimiento Celular/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/metabolismo , Proteínas de Neoplasias , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/enzimología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos
5.
Blood ; 136(14): 1657-1669, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32573700

RESUMEN

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.


Asunto(s)
Antineoplásicos/farmacología , Crizotinib/farmacología , Resistencia a Antineoplásicos/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Linfoma Anaplásico de Células Grandes/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/genética , Antineoplásicos/uso terapéutico , Sistemas CRISPR-Cas , Línea Celular , Crizotinib/uso terapéutico , Relación Dosis-Respuesta a Droga , Edición Génica , Expresión Génica , Humanos , Inmunohistoquímica , Subunidad alfa del Receptor de Interleucina-10/metabolismo , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Modelos Biológicos , Nucleofosmina , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos
6.
Int J Cancer ; 148(3): 731-747, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33034050

RESUMEN

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein µ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRß) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.


Asunto(s)
Cristalinas/genética , Cristalinas/metabolismo , Regulación hacia Abajo , Neoplasias de la Próstata/patología , Transducción de Señal , Línea Celular Tumoral , Colina/administración & dosificación , Colina/análogos & derivados , Estudios de Cohortes , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metabolómica , Estadificación de Neoplasias , Células PC-3 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Hormona Tiroidea/genética , Análisis de Secuencia de ARN , Análisis de Matrices Tisulares , Triyodotironina/antagonistas & inhibidores , Triyodotironina/metabolismo , Cristalinas mu
7.
Haematologica ; 106(6): 1693-1704, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32327503

RESUMEN

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.


Asunto(s)
Linfoma Anaplásico de Células Grandes , Línea Celular Tumoral , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Mutación , Recurrencia Local de Neoplasia , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor Notch1/genética , Secuenciación del Exoma
8.
Blood ; 132(22): 2389-2400, 2018 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-30213873

RESUMEN

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.


Asunto(s)
Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Linfoma Folicular/genética , MicroARNs/genética , Proteínas Represoras/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación hacia Abajo , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Activación Transcripcional , Regulación hacia Arriba
9.
Haematologica ; 105(2): 435-447, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31123029

RESUMEN

Recurrent gain-of-function mutations in the transcription factors STAT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8+ T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.


Asunto(s)
Leucemia , Linfoma de Células T Periférico , Animales , Linfocitos T CD8-positivos/metabolismo , Citocinas , Humanos , Linfoma de Células T Periférico/genética , Ratones , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Proteínas Supresoras de Tumor
10.
Blood ; 130(23): 2499-2503, 2017 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-28972014

RESUMEN

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.


Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Adulto , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Resistencia a Antineoplásicos , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Sulfonamidas/farmacología , Resultado del Tratamiento
11.
Cytokine ; 124: 154569, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-30389231

RESUMEN

The rising prevalence of obesity came along with an increase in associated metabolic disorders in Western countries. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and is linked to primary stages of liver cancer development. Growth hormone (GH) regulates various vital processes such as energy supply and cellular regeneration. In addition, GH regulates various aspects of liver physiology through activating the Janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 pathway. Consequently, disrupted GH - JAK2 - STAT5 signaling in the liver alters hepatic lipid metabolism and is associated with NAFLD development in humans and mouse models. Interestingly, while STAT5 as well as JAK2 deficiency correlates with hepatic lipid accumulation, recent studies suggest that these proteins have unique ambivalent functions in chronic liver disease progression and tumorigenesis. In this review, we focus on the consequences of altered GH - JAK2 - STAT5 signaling for hepatic lipid metabolism and liver cancer development with an emphasis on lessons learned from genetic knockout models.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Hormona del Crecimiento/metabolismo , Janus Quinasa 2/metabolismo , Neoplasias Hepáticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factor de Transcripción STAT5/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Janus Quinasa 2/genética , Metabolismo de los Lípidos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Receptores de Glucocorticoides/metabolismo , Factor de Transcripción STAT5/genética , Transducción de Señal/genética
12.
Blood ; 125(1): 124-32, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25359993

RESUMEN

Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALK gene (ALK(+) and ALK(-) ALCL). The interferon regulatory factor 4 (IRF4) is known to be highly expressed in both ALK(+) and ALK(-) ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear. Here we show that ALCLs of both subtypes are addicted to IRF4 signaling, as knockdown of IRF4 by RNA interference was toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo. Gene expression profiling after IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Furthermore, our analyses revealed that MYC is a primary target of IRF4, identifying a novel regulatory mechanism of MYC expression and its target gene network in ALCL. MYC, itself, is essential for ALCL survival, as both knockdown of MYC and pharmacologic inhibition of MYC signaling were toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC may represent a promising target for future therapies.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Factores Reguladores del Interferón/metabolismo , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Linfoma/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Interferencia de ARN , Retroviridae/metabolismo , Transducción de Señal
13.
J Zoo Wildl Med ; 48(4): 1154-1164, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29297805

RESUMEN

Under the project of "Human-Led Migration," the authors had the unique opportunity to accompany hand-raised northern bald Iibises (NBIs; Geronticus eremita) during migration, which occurred in stages from Bavaria, Germany, to southern Tuscany, Italy. The aim of this study was to investigate the immediate effects of flight, with respect to flight duration, and the more delayed recovery effects on hematologic variables. A total of 31 birds were sampled. Blood samples were taken immediately before takeoff, after landing, and 1 day after the flight. Hematocrit was determined and blood smears were prepared to estimate the total white blood count (tWBC) with leukocyte concentrations (absolute [abs.]) and differential blood cell count (%). Postflight, significant decreases in hematocrit, tWBC, lymphocytes (abs., %), heterophils (abs.), eosinophils (abs., %), and monocytes (abs.) were observed. In contrast, heterophils (%), basophils (%), and the heterophil/lymphocyte (H/L) ratio increased significantly. With increasing flight duration, the H/L ratio increased further. One day postflight, there were still significant decreases in tWBC, lymphocytes (abs.), and eosinophils (abs., %) and significant increases in heterophils (%) and the H/L ratio. The hematocrit dropped even further. These data show that the decrease of tWBC is mainly caused by the lymphocyte fraction and that NBIs need more than 1 day to reverse the postflight changes in some hematologic values. Hematocrit changes postflight and on the recovery day are most likely to be explained by hemodynamics and the metabolic and hormonal changes caused by flight. The hematologic changes postflight in NBIs were largely consistent with those of other birds, but they differed from humans and mammals postexercise mainly in the levels of tWBC, heterophils (matching neutrophils in mammals), and lymphocytes.


Asunto(s)
Migración Animal/fisiología , Aves/sangre , Aves/fisiología , Vuelo Animal/fisiología , Animales , Femenino , Alemania , Masculino
14.
Biol Chem ; 397(8): 777-90, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27078672

RESUMEN

Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-ß (Aß) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aß generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aß region, thus preventing the generation of N-terminally truncated Aß.


Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/análisis , Células Cultivadas , Células HEK293 , Humanos , Cinética , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo
15.
Cytokine ; 87: 26-36, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27349799

RESUMEN

In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity. Inhibitors of the JAK/STAT pathway are used for treatment of autoimmune diseases, such as rheumatoid arthritis or psoriasis. Aberrant JAK/STAT signaling has been identified to contribute to cancer progression and metastatic development. Targeting of JAK/STAT pathway is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas. Notably, newly identified regulators of JAK/STAT signaling, the non-coding RNAs transcripts and their role as important targets and potential clinical biomarkers are highlighted in this review. In addition to the established role of the JAK/STAT signaling pathway in traditional cytokine signaling the non-coding RNAs add yet another layer of hidden regulation and function. Understanding the crosstalk of non-coding RNA with JAK/STAT signaling in cancer is of critical importance and may result in better patient stratification not only in terms of prognosis but also in the context of therapy.


Asunto(s)
Citocinas/metabolismo , Quinasas Janus/metabolismo , Neoplasias/metabolismo , ARN no Traducido/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Animales , Genoma , Humanos , Masculino , Ratones , Neoplasias/terapia , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Sarcoma/metabolismo , Sarcoma/terapia
16.
Exp Dermatol ; 25(4): 305-10, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-26739431

RESUMEN

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung or even the brain. We have shown that JunB(Δep) mice develop a SLE phenotype linked to increased epidermal Interleukin (IL)-6 secretion. Blocking of IL-6 receptor alpha (IL-6Rα) is considered as therapeutic strategy for the treatment of SLE. JunB(Δep) and wild-type mice were treated for short (5 weeks) or long term (21 weeks) with the IL-6Rα-blocking antibody MR16-1. Skin and kidney of mice were investigated by histology and immunofluorescence, and in addition, kidneys were analysed by electron microscopy. Furthermore, soluble IL-6R (sIL-6R), antihistone and antinucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16-1 resulted in significant improvement of SLE-like skin lesions in JunB(Δep) mice, compared to untreated mice. The sIL-6R amount upon long-term treatment with MR16-1 was significantly higher in JunB(Δep) versus untreated JunB(Δep) (P = 0.034) or wild-type mice (P = 0.034). MR16-1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher antihistone (P = 0.028) and antinucleosome antibody levels (P = 0.028) were measured in MR16-1-treated JunB(Δep) mice after treatment compared to levels before therapy. In conclusion, blockade of IL-6Rα improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune-mediated kidney pathology. Inhibition of IL-6R signalling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies.


Asunto(s)
Regulación de la Expresión Génica , Subunidad alfa del Receptor de Interleucina-6/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-6/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Factores de Transcripción/genética , Albúminas/análisis , Animales , Anticuerpos Antinucleares/inmunología , Peso Corporal , Modelos Animales de Enfermedad , Inmunoglobulina G/inmunología , Inmunoglobulinas/metabolismo , Riñón/metabolismo , Riñón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Transducción de Señal , Piel/metabolismo , Piel/patología , Enfermedades de la Piel/patología
17.
J Pathol ; 236(4): 445-56, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25820993

RESUMEN

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPß and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPß and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPß target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).


Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 5 , Linfoma Anaplásico de Células Grandes/genética , MicroARNs/genética , Translocación Genética , Quinasa de Linfoma Anaplásico , Animales , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Estudios de Casos y Controles , Caspasa 3/metabolismo , Línea Celular Tumoral , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Terapia Genética/métodos , Humanos , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/terapia , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/metabolismo , Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas Receptoras/deficiencia , Proteínas Tirosina Quinasas Receptoras/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Glia ; 63(4): 626-34, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25451814

RESUMEN

Microglia are resident immune cells in the brain and exert important functions in the regulation of inflammatory processes during infection or cellular damage. Upon activation, microglia undergo complex morphological and functional transitions, including increased motility, phagocytosis and cytokine secretion. Recent findings indicate that exosomes, small vesicles that derive from fusion of multivesicular bodies with the plasma membrane, are involved in secretion of certain cytokines. The presence of specific receptors on the surface of microglia suggests communication with neurons by neurotransmitters. Here, we demonstrate expression of serotonin receptors, including 5-HT2a,b and 5-HT4 in microglial cells and their functional involvement in the modulation of exosome release by serotonin. Our data demonstrate the involvement of cAMP and Ca(2+) dependent signaling pathways in the regulation of exosome secretion. Co-culture of microglia with embryonic stem cell-derived serotonergic neurons further demonstrated functional signaling between neurons and microglia. Together, these data provide evidence for neurotransmitter-dependent signaling pathways in microglial cells that regulate exosome release.


Asunto(s)
Exosomas/metabolismo , Microglía/citología , Microglía/metabolismo , Serotonina/metabolismo , Transducción de Señal/fisiología , Animales , Línea Celular , Técnicas de Cocultivo , Ratones , Neuronas/citología , Neuronas/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptores de Serotonina 5-HT4/metabolismo , Células Madre/citología
19.
Haematologica ; 99(8): 1285-91, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25082786

RESUMEN

A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.


Asunto(s)
Bases de Datos Factuales , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Factuales/tendencias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
20.
Cell Rep Med ; 5(3): 101472, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38508140

RESUMEN

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.


Asunto(s)
Linfoma Anaplásico de Células Grandes , Transducción de Señal , Adulto , Niño , Humanos , Transducción de Señal/genética , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Transformación Celular Neoplásica , Carcinogénesis/genética , Factor de Transcripción STAT3/genética
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