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Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

2014-06Journal article Open access
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dc.contributor.authorGomes, AM
dc.contributor.authorSoares, M
dc.contributor.authorRibeiro, P
dc.contributor.authorCaldas, J
dc.contributor.authorPóvoa, V
dc.contributor.authorMartins, L
dc.contributor.authorMelão, A
dc.contributor.authorSerra-Caetano, A
dc.contributor.authorBotelho de Sousa, A
dc.contributor.authorLacerda, J
dc.contributor.authorBarata, J
dc.date.accessioned2016-05-04T13:07:03Z
dc.date.available2016-05-04T13:07:03Z
dc.date.issued2014-06
dc.description.abstractAdult 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.pt_PT
dc.identifier.citationHaematologica. 2014 Jun;99(6):1062-8pt_PT
dc.identifier.doi10.3324/haematol.2013.096438pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/2464
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPubmed Centralpt_PT
dc.subjectHSAC ONCpt_PT
dc.subjectCase-Control Studiespt_PT
dc.subjectCasein Kinase II/antagonists & inhibitorspt_PT
dc.subjectCasein Kinase II/metabolismpt_PT
dc.subjectChromosome Aberrationspt_PT
dc.subjectCell Linept_PT
dc.subjectEnzyme Activationpt_PT
dc.subjectGene Expressionpt_PT
dc.subjectImmunohistochemistrypt_PT
dc.subjectJanus Kinases/metabolismpt_PT
dc.subjectPTEN Phosphohydrolase/geneticspt_PT
dc.subjectPTEN Phosphohydrolase/metabolismpt_PT
dc.subjectPhosphatidylinositol 3-Kinases/antagonists & inhibitorspt_PT
dc.subjectPhosphatidylinositol 3-Kinases/metabolismpt_PT
dc.subjectPrecursor B-Cell Lymphoblastic Leukemia-Lymphoma/geneticspt_PT
dc.subjectPrecursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolismpt_PT
dc.subjectProtein Kinase Inhibitors/pharmacologypt_PT
dc.subjectProto-Oncogene Proteins c-akt/metabolismpt_PT
dc.subjectSTAT Transcription Factors/metabolismpt_PT
dc.subjectSignal Transduction/drug effectspt_PT
dc.titleAdult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levelspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1068pt_PT
oaire.citation.startPage1062pt_PT
oaire.citation.titleHaematologicapt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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