title: Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: A Margarida
authors.initials: AM
authors.lastname: Gomes
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria V D
authors.initials: MV
authors.lastname: Soares
authors.affiliation: Hospital dos Capuchos, Lisboa, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Ribeiro
authors.affiliation: Hospital dos Capuchos, Lisboa, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Caldas
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Vanda
authors.initials: V
authors.lastname: Póvoa
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Leila R
authors.initials: LR
authors.lastname: Martins
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Alice
authors.initials: A
authors.lastname: Melão
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Serra-Caetano
authors.affiliation: Hospital dos Capuchos, Lisboa, Portugal.
authors.forename: Aida B
authors.initials: AB
authors.lastname: de Sousa
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal Hospital de Santa Maria, Lisboa, Portugal.
authors.forename: João F
authors.initials: JF
authors.lastname: Lacerda
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal joao_barata@fm.ul.pt.
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002869:Chromosome Aberrations; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D047390:Casein Kinase II; D053612:Janus Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050791:STAT Transcription Factors; C494929:PTEN protein, human