title: Targeting nonclassical oncogenes for therapy in T-ALL.
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.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Prem S
authors.initials: PS
authors.lastname: Subramaniam
authors.forename: Dosh W
authors.initials: DW
authors.lastname: Whye
authors.forename: Evgeni
authors.initials: E
authors.lastname: Efimenko
authors.forename: Jianchung
authors.initials: J
authors.lastname: Chen
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Adam
authors.initials: A
authors.lastname: Kashishian
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Thompson
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Utpal P
authors.initials: UP
authors.lastname: Davé
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Diacovo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D011687:Purines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011687:Purines; D052999:Quinazolinones; C572883:CAL-130; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse