Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels
| Autor: | João T. Barata, Ana Serra-Caetano, Alice Melão, A. Margarida Gomes, Vanda Póvoa, Patrícia Ribeiro, Aida Botelho de Sousa, Leila R. Martins, Maria V. D. Soares, João F. Lacerda, Joana Caldas |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Gene Expression HSAC ONC Phosphatidylinositol 3-Kinases 0302 clinical medicine hemic and lymphatic diseases Signal Transduction/drug effects Casein Kinase II/metabolism Proto-Oncogene Proteins c-akt/metabolism Casein Kinase II Phosphoinositide-3 Kinase Inhibitors Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism 0303 health sciences biology PTEN Phosphohydrolase/genetics Hematology Articles Middle Aged Immunohistochemistry 3. Good health Leukemia STAT Transcription Factors 030220 oncology & carcinogenesis Lipid phosphatase activity Janus Kinases/metabolism Female Signal transduction Casein kinase 2 Phosphatidylinositol 3-Kinases/metabolism Signal Transduction Adult STAT Transcription Factors/metabolism Adolescent PTEN Phosphohydrolase/metabolism Phosphatidylinositol 3-Kinases/antagonists & inhibitors Cell Line Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics 03 medical and health sciences Young Adult Precursor B-Cell Lymphoblastic Leukemia-Lymphoma medicine PTEN Humans Kinase activity Protein Kinase Inhibitors PI3K/AKT/mTOR pathway 030304 developmental biology Aged Janus Kinases Chromosome Aberrations PTEN Phosphohydrolase medicine.disease Enzyme Activation Case-Control Studies Protein Kinase Inhibitors/pharmacology Casein Kinase II/antagonists & inhibitors Cancer research biology.protein Janus kinase Proto-Oncogene Proteins c-akt |
| Zdroj: | Haematologica Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) |
| Popis: | © 2014 Ferrata Storti Foundation. This is an open-access paper 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. This study was supported by grant PTDC/IC/83023/2007, from Fundação para a Ciência e a Tecnologia (FCT). A.M.G. and V.P. received BI fellowships from FCT. L.R.M. and A.M. received a post-doctoral and a PhD fellowship, respectively, both from FCT. |
| Databáze: | OpenAIRE |
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