Showing papers by "João T. Barata published in 2014"
TL;DR: It is found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls, and it is suggested that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.
Abstract: Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.
75 citations
TL;DR: Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia is inhibited by a second substance called CK2A, which is cytotoxic to lymphocytes and excites the immune system to attack these cells.
Abstract: Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia
72 citations
TL;DR: The key to evaluating the real impact of PTEN as a 'quasi-insufficient' tumour suppressor must rely on the complete understanding ofPTEN's 'functional dose', incorporating the multiple layers of PT EN regulation in the cell that are ultimately compromised in a given cancer.
71 citations
TL;DR: It is shown that PTEN is inactivated by small deletions affecting a few exons in 8% of pediatric T-ALL patients, and ongoing RAG activity may actively contribute to the acquisition of preleukemic hits, clonal diversification, and disease progression.
66 citations
TL;DR: Analysis of the therapeutic potential of NVP-BKM120, an orally bioavailable 2,6-dimorpholino pyrimidine derivative, indicates that it may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.
Abstract: Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.
63 citations
Ikerbasque1, St. Jude Children's Research Hospital2, Instituto de Medicina Molecular3, University of the Basque Country4, Complutense University of Madrid5, Queen's University6, University of South Florida7, Utrecht University8, Johns Hopkins University School of Medicine9, Charité10, Case Western Reserve University11, Ludwig Institute for Cancer Research12, University of Texas Southwestern Medical Center13, Worcester Polytechnic Institute14, Icahn School of Medicine at Mount Sinai15, Memorial Sloan Kettering Cancer Center16, Chonnam National University17, National Institute of Standards and Technology18, Hospital Universitari Arnau de Vilanova19, Harvard University20, University of Ferrara21, University of Santiago de Compostela22, University of Massachusetts Medical School23, University of Toronto24, University of Southern California25, Akita University26, University of Melbourne27, Cold Spring Harbor Laboratory28, Pasteur Institute29, Imperial College London30, University of California, Los Angeles31, Heriot-Watt University32
TL;DR: A unifying nomenclature and amino acid numbering for this previously uncharacterized form of PTEN has been proposed, that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site.
Abstract: The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.
56 citations
TL;DR: It is shown that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells, and provides pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.
Abstract: // Leila R. Martins 1 , Yasser Perera 2 , Paulo Lucio 3 , Maria G. Silva 3 , Silvio E. Perea 2 , Joao T. Barata 1 1 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; 2 Centro de Ingenieria Genetica y Biotecnologia, Havana, Cuba; 3 CEDOC, Faculdade de Ciencias Medicas, FCM, Universidade Nova de Lisboa and Instituto Portugues de Oncologia, Lisbon, Portugal. Correspondence: Joao T. Barata, email: // Keywords : Chronic Lymphocytic Leukemia, CLL, Casein kinase 2, CK2, CIGB-300, Signaling therapies. Received : October 17, 2013 Accepted : December 11, 2013 Published : December 13, 2013 Abstract Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identification of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efficacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL.
34 citations
TL;DR: The discovery that PTEN regulates L SCs and HSCs through different mechanisms demonstrated that it is possible to identify pathways that differentially impact leukemia and normal stem cell function and opened new therapeutic perspectives for the selective elimination of LSCs.
Abstract: Leukemia stem cells (LSCs) are considered responsible for leukemia initiation, relapse and resistance to chemotherapy. These cells have self-renewal capacity and originate the other cells in the leukemia pool. Therefore, in order to completely eradicate leukemia cells and consequently cure the disease, therapies should in principle necessarily target LSCs. However, the fact that LSCs share functional and phenotypic properties with normal hematopoietic stem cells (HSCs) poses a significant challenge: how to target LSCs without damaging normal HSCs and compromising hematopoiesis? The discovery that PTEN regulates LSCs and HSCs through different mechanisms, demonstrated that it is possible to identify pathways that differentially impact leukemia and normal stem cell function and opened new therapeutic perspectives for the selective elimination of LSCs. In this review, we briefly discuss the mechanisms that regulate PTEN function in LSCs and HSCs and their potential for the development of LSC-targeted therapies.
34 citations
TL;DR: The results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAff-R expression is controlled by BAFF binding.
Abstract: B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets
21 citations
TL;DR: Overal, it is shown that bone marrow stroma protects MPN cells from the cytotoxic effects of two clinically effective pharmacological agents of different classes: Vorinostat and Ruxolitinib.
2 citations