Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, ACUTE LYMPHOBLASTIC-LEUKEMIA, CELL-SPECIFIC DELETION, HIGH-FREQUENCY, PI3K ISOFORM, PTEN, PATHWAY, PROLIFERATION, INHIBITOR, MUTATIONS, 3-KINASE, Animals, Antineoplastic Agents, Apoptosis, Binding Sites, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Class I Phosphatidylinositol 3-Kinases, Class Ib Phosphatidylinositol 3-Kinase, Drug Design, Gene Silencing, Humans, Mice, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Isoforms, Purines, Quinazolinones, 1109 Neurosciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

Abstract:

Constitutive phosphoinositide 3-kinase (PI3K)/Akt activation is common in T cell acute lymphoblastic leukemia (T-ALL). Although four distinct class I PI3K isoforms (α, β, γ, δ) could participate in T-ALL pathogenesis, none has been implicated in this process. We report that in the absence of PTEN phosphatase tumor suppressor function, PI3Kγ or PI3Kδ alone can support leukemogenesis, whereas inactivation of both isoforms suppressed tumor formation. The reliance of PTEN null T-ALL on the combined activities of PI3Kγ/δ was further demonstrated by the ability of a dual inhibitor to reduce disease burden and prolong survival in mice as well as prevent proliferation and promote activation of proapoptotic pathways in human tumors. These results support combined inhibition of PI3Kγ/δ as therapy for T-ALL.