Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia

The Human T-cell Leukemia virus type 1 (HTLV-1) causes an array of pathologies, the most aggressive of which is adult T-cell leukemia (ATL), a fatal blood malignancy with dismal prognosis. The progression of these diseases is partly ascribed to the failure of the immune system in controlling the spread of virally infected cells. HTLV-1 infected subjects, whether asymptomatic carriers or symptomatic patients are prone to opportunistic infections. An increasing body of literature emphasizes the interplay between HTLV-1, its associated pathologies, and the pivotal role of the host innate and adoptive immune system, in shaping the progression of HTLV-1 associated diseases and their response to therapy. In this review, we will describe the modalities adopted by the malignant ATL cells to subvert the host innate immune response with emphasis on the role of the two viral oncoproteins Tax and HBZ in this process. We will also provide a comprehensive overview on the function of innate immunity in the therapeutic response to chemotherapy, anti-viral or targeted therapies in the pre-clinical and clinical settings

Dietary polyphenols display zinc ionophore activity and modulate zinc signaling in hepatocarcinoma cells

El zinc és el metall de transició més abundant després del ferro a totes les cèl·lules, i un micronutrient essencial, presentant diverses funcions en sistemes biològics. D'altra banda, els polifenols de la dieta són micronutrients bioactius que mostren nombrosos beneficis per a la salut, com ara activitat antitumoral i neuroprotectora. Anteriors treballs del nostre grup d'investigació han demostrat que els polifenols interaccionen amb cations de zinc i tenen la capacitat de modular l'expressió de diferents gens implicats en l'homeòstasi d'aquest. En aquest treball van ser usats els flavonoides gal·lat d’Epigalocatequina i Quercetina com a models per polifenols hidrofílics i lipofílics respectivament, observant-se que, un cop combinats amb el zinc, presenten activitat ionófora per aquest metall en un sistema liposomal, similar a l'efecte del Clioquinol, fàrmac utilitzat en teràpies anti-càncer i anti-Alzheimer. A través d'aquest mecanisme, s'augmenten el pool de zinc làbil citoplasmàtic, intercanviable i de senyalització en el model de carcinoma hepatocel·lular Hepa 1-6. Per tant, els polifenols de la dieta es poden afegir a l'arsenal de fàrmacs que modulen l'homeòstasi del zinc i regulen les vies biològiques dependents d'aquest. Com a prova d'aquest principi, hem demostrat aquí, que en concentracions molt baixes, el gal·lat d’Epigalocatequina i la Quercetina quan es combinen amb el zinc, poden activar o inhibir la fosforilació d'Akt en cèl·lules Hepa 1-6. A més, vam demostrar que la Quercetina desencadena l’apoptosi en el carcinoma hepatocel·lular Hepa 1-6 de manera dependent de zinc.El zinc es el metal de transición más abundante después del hierro en todas las células, y un micronutriente esencial, presentando diversas funciones en sistemas biológicos. Por otra parte, los polifenoles de la dieta son micronutrientes bioactivos que muestran numerosos beneficios para la salud, tales como actividad antitumoral y neuroprotectora. Anteriores trabajos de nuestro grupo de investigación han demostrado que los polifenoles interaccionan con cationes de zinc y tienen la capacidad de modular la expresión de diferentes genes implicados en la homeostasis de éste. En este trabajo fueron usados los flavonoides galato de Epigalocatequina y Quercetina como modelos para polifenoles hidrofílicos y lipofílicos respectivamente, observándose que, una vez combinados con zinc, presentan actividad ionófora para este metal en un sistema liposomal, similar al efecto del Clioquinol, fármaco utilizado en terapias anti-cáncer y anti-Alzheimer. A través de este mecanismo, se aumentan el pool de zinc lábil citoplasmático, intercambiable y de señalización en el modelo de carcinoma hepatocelular Hepa 1-6. Por lo tanto, los polifenoles de la dieta se pueden añadir al arsenal de fármacos que modulan la homeostasis del zinc y regulan las vías biológicas dependientes de éste. Como prueba de este principio, hemos demostrado aquí, que en concentraciones muy bajas, el galato de Epigalocatequina y la Quercetina cuando se combinan con zinc, pueden activar o inhibir la fosforilación de Akt en células Hepa 1-6. Además, demostramos que la Quercetina desencadena apoptosis en el carcinoma hepatocelular Hepa 1-6 de manera dependiente de zinc.Zinc is the most abundant transition metal after iron in all cells and an essential micronutrient, displaying many functions in biological systems. On the other hand, dietary polyphenols are bioactive micronutrients that display many health benefits, such as antitumor and neuroprotective activity. Previous work by our research group has shown that polyphenols interact with zinc cations and have the ability to modulate the expression of different genes involved in zinc homeostasis. In this work, using the flavonoids Epigallocatechin-gallate and Quercetin as a model for hydrophilic and lipophilic polyphenols respectively, we show that, once polyphenols are combined with zinc, they display a zinc ionophore activity in a liposomal system, similar to the anti-cancer and anti-Alzheimer drug Clioquinol. Through this mechanism, they increase the labile, interchangeable and signaling pool of cytoplasmic zinc in the hepatocellular carcinoma cells Hepa 1-6 model. Thus, natural dietary polyphenols can be added to the arsenal of drugs that may be used to modulate zinc homeostasis and regulate zinc-dependent biological pathways. As a probe of this principle, we have shown here that at remarkably low concentrations, Epigallocatechin-gallate and Quercetin when combined with zinc, may activate or inhibit Akt-phosphorylation in Hepa 1-6 cells. In addition, we demonstrate that Quercetin triggers apoptosis in the hepatocellular carcinoma Hepa 1-6 cell line in a zinc-dependent way

A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients

International audiencen.

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML

TRAF5-mediated Tax ubiquitination modulates IKK phosphorylation but not binding to NEMO

International audienc

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL

Essential requirements for setting up a stem cell processing laboratory

The Graft Processing subcommittee of the Worldwide Network for Blood and Marrow Transplantation wrote this guideline to assist physicians and laboratory technologists with the setting up of a cell processing laboratory (CPL) to support a hematopoietic stem cell transplant program, thereby facilitating the start-up of a transplant program in a new location and improving patient access to transplantation worldwide. This guideline describes the minimal essential features of designing such a laboratory and provides a list of equipment and supply needs and staffing recommendations. It describes the typical scope of services that a CPL is expected to perform, including product testing services, and discusses the basic principles behind the most frequent procedures. Quality management (QM) principles specific to a CPL are also discussed. References to additional guidance documents that are available worldwide to assist with QM and regulatory compliance are also provided. © 2014 Macmillan Publishers Limited All rights reserved

Predominant role of Tax sumoylation in Tax-induced NF-kB activation in T cells

International audiencen.