title: The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia.
abstract: The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycolysis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.
authors: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Rui D
authors: RD
authors: Mendes
authors: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Kirsten
authors: K
authors: Canté-Barrett
authors: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors: Rob
authors: R
authors: Pieters
authors: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands j.meijerink@erasmusmc.nl.
authors: Jules P P
authors: JP
authors: Meijerink
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051881:Receptor, Notch1; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D053829:Amyloid Precursor Protein Secretases