Publicação
Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels
| Resumo: | 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. |
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| Autores principais: | Gomes, AM |
| Outros Autores: | Soares, M; Ribeiro, P; Caldas, J; Póvoa, V; Martins, L; Melão, A; Serra-Caetano, A; Botelho de Sousa, A; Lacerda, J; Barata, J |
| Assunto: | HSAC ONC Case-Control Studies Casein Kinase II/antagonists & inhibitors Casein Kinase II/metabolism Chromosome Aberrations Cell Line Enzyme Activation Gene Expression Immunohistochemistry Janus Kinases/metabolism PTEN Phosphohydrolase/genetics PTEN Phosphohydrolase/metabolism Phosphatidylinositol 3-Kinases/antagonists & inhibitors Phosphatidylinositol 3-Kinases/metabolism Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-akt/metabolism STAT Transcription Factors/metabolism Signal Transduction/drug effects |
| Ano: | 2014 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Centro Hospitalar de Lisboa Central, EPE (CHLC) |
| Idioma: | inglês |
| Origem: | Repositório do Centro Hospitalar de Lisboa Central, EPE |
| Resumo: | 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. |
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