Targeting nonclassical oncogenes for therapy in T-ALL.

Subramaniam PS, Whye DW, Efimenko E, Chen J, Tosello V, De Keersmaecker K, Kashishian A, Thompson MA, Castillo M, Cordon-Cardo C, Davé UP, Ferrando A, Lannutti BJ, Diacovo TG
Cancer Cell. 2012 21 (4): 459-72

PMID: 22516257 · DOI:10.1016/j.ccr.2012.02.029

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (20)

Animals Antineoplastic Agents Apoptosis Binding Sites Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Class Ib Phosphatidylinositol 3-Kinase Class I Phosphatidylinositol 3-Kinases Drug Design Gene Silencing Humans Mice Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Protein Isoforms PTEN Phosphohydrolase Purines Quinazolinones

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