Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors.
T-cell acute lymphoblastic leukemia (T-ALL) patients frequently display NOTCH1 activating mutations and Notch can transcriptionally down-regulate the tumor suppressor PTEN. However, it is not clear whether NOTCH1 mutations associate with decreased PTEN expression in primary T-ALL. Here, we compared patients with or without NOTCH1 mutations and report that the former presented higher MYC transcript levels and decreased PTEN mRNA expression. We recently showed that T-ALL cells frequently display CK2-mediated PTEN phosphorylation, resulting in PTEN protein stabilization and concomitant functional inactivation. Accordingly, the T-ALL samples analyzed, irrespectively of their NOTCH1 mutational status, expressed significantly higher PTEN protein levels than normal controls. To evaluate the integrated functional impact of Notch transcriptional and CK2 post-translational inactivation of PTEN, we treated T-ALL cells with both the gamma-secretase inhibitor DAPT and the CK2 inhibitors DRB/TBB. Our data suggest that combined use of gamma-secretase and CK2 inhibitors may have therapeutic potential in T-ALL.
Silva
Ana
A
Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University Medical School, Av Prof Egas Moniz, 1649-028 Lisboa, Portugal.
Jotta
Patrícia Y
PY
Silveira
André B
AB
Ribeiro
Daniel
D
Brandalise
Silvia R
SR
Yunes
J Andrés
JA
Barata
João T
JT
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002648:Child; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology
C405354:4,5,6,7-tetrabromobenzotriazole; D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D014230:Triazoles; D004004:Dichlororibofuranosylbenzimidazole; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053829:Amyloid Precursor Protein Secretases