The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells characterized by the accumulation of several genetic and epigenetic mutations. Despite the progressive understanding of the molecular heterogeneity of the disease, the survival rate of patients older than 60 years old remains poor. Therefore, it is necessary to develop an effective treatment strategy for those patients in order to beat the disease and improve life quality. Reversible phosphorylation has been widely studied over the last years, and the deregulation of kinases and phosphatase have been verified to have a huge impact in leukemogenesis. Inactivation of the tumor-suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, constituting a promising target for cancer therapy. There are several PP2A inactivation mechanisms. However, overexpression of SET or cancerous inhibitors of PP2A, both endogenous inhibitors of PP2A, are recurrent events in AML patients, leading to the inactivation of the phosphatase PP2A. Preclinical studies show that PP2A reactivation using PP2A-activating drugs (PADs) manage to stop the development of the disease, and its combination with conventional chemotherapy and tyrosine kinase inhibitors have a synergistic cytotoxic effects. Recent studies have demonstrated that specifically activation of PP2A subunits, target crucial pathogenic drivers, increasing the efficacy of conventional treatments and opening new possibilities for personalized treatment in AML patients, especially in cases of PP2A deregulation. Here, we review the role of PP2A in AML as well as its drugable options

High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD)

Growing clinical and experimental evidence suggests that sterile inflammation contributes to alcoholic liver disease (ALD). High mobility group box-1 (HMGB1) is highly induced during liver injury; however, a link between this alarmin and ALD has not been established. Thus, the aim of this work was to determine whether HMGB1 contributes to the pathogenesis of ALD. Liver biopsies from patients with ALD showed a robust increase in HMGB1 expression and translocation, which correlated with disease stage, compared with healthy explants. Similar findings were observed in chronic ethanol-fed wild-type (WT) mice. Using primary cell culture, we validated the ability of hepatocytes from ethanol-fed mice to secrete a large amount of HMGB1. Secretion was time- and dose-dependent and responsive to prooxidants and antioxidants. Selective ablation of Hmgb1 in hepatocytes protected mice from alcohol-induced liver injury due to increased carnitine palmitoyltransferase-1, phosphorylated 5′AMP-activated protein kinase-α, and phosphorylated peroxisome proliferator-activated receptor-α expression along with elevated LDL plus VLDL export. Native and post-translationally modified HMGB1 were detected in humans and mice with ALD. In liver and serum from control mice and in serum from healthy volunteers, the lysine residues within the peptides containing nuclear localization signals (NLSs) 1 and 2 were non-acetylated, and all cysteine residues were reduced. However, in livers from ethanol-fed mice, in addition to all thiol/non-acetylated isoforms of HMGB1, we observed acetylated NLS1 and NLS2, a unique phosphorylation site in serine 35, and an increase in oxidation of HMGB1 to the disulfide isoform. In serum from ethanol-fed mice and from patients with ALD, there was disulfide-bonded hyperacetylated HMGB1, disulfide-bonded non-acetylated HMGB1, and HMGB1 phosphorylated in serine 35. Hepatocytes appeared to be a major source of these HMGB1 isoforms. Thus, hepatocyte HMGB1 participates in the pathogenesis of ALD and undergoes post-translational modifications (PTMs) that could condition its toxic effects

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Objective: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression. Design and results: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn−/− mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K–pAkt1/2/ 3 pathway to upregulate collagen-I

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38 beta is a common event in AML. We provide evidence that p38 beta potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38 beta/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation

Innovación pedagógica vía TIC para la mejora de la calidad educativa en la FIUBA

Se propone la implementación de una red social Web para uso de docentes y alumnos del Departamento de Computación de la FIUBA que posibilite la organización de cursos y la instrumentación de modalidades de enseñanza y aprendizaje colaborativos que permita incluir actividades de estimulación de la creatividad. También, se brindaría acceso a visitantes WEB con posibilidad de participar en foros de la red y de los cursos para intercambio de ideas y realización de consultas.Eje: Tecnología informática aplicada en educaciónRed de Universidades con Carreras en Informática (RedUNCI

Nuevas formas de construcción del conocimiento: redes sociales

El objetivo de esta línea de investigación es el estudio del aporte que las redes sociales tienen en la generación y comunicación de saberes. Para ello se estudia el uso de distintas aplicaciones y herramientas tecnológicas y su integración con la enseñanza. Así como también el grado de penetración de dichas herramientas entre los alumnos de las distintas carreras de la FIUBA. Abordando posteriormente la implementación de un entorno de enseñanza con las características de red social.Eje: Tecnología Informática Aplicada en EducaciónRed de Universidades con Carreras en Informática (RedUNCI

Diseño y elaboración de material estandarizado para el desarrollo de habilidades sociales de comunicación

Se presenta un proyecto de desarrollo de plantillas estandarizadas para el desarrollo de habilidades sociales y competencias para la comunicación eficaz de los alumnos de Ingeniería de la Universidad de Buenos Aires.Eje: Innovación en Educación InformáticaRed de Universidades con Carreras en Informática (RedUNCI

Diseño y elaboración de material estandarizado para el desarrollo de habilidades sociales de comunicación

Se presenta un proyecto de desarrollo de plantillas estandarizadas para el desarrollo de habilidades sociales y competencias para la comunicación eficaz de los alumnos de Ingeniería de la Universidad de Buenos Aires.Eje: Innovación en Educación InformáticaRed de Universidades con Carreras en Informática (RedUNCI

Diseño y elaboración de material estandarizado para el desarrollo de habilidades sociales de comunicación

Se presenta un proyecto de desarrollo de plantillas estandarizadas para el desarrollo de habilidades sociales y competencias para la comunicación eficaz de los alumnos de Ingeniería de la Universidad de Buenos Aires.Eje: Innovación en Educación InformáticaRed de Universidades con Carreras en Informática (RedUNCI

Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation–related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies