title: Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia.
abstract: The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been shown to be frequently activated in blast cells from patients with acute myeloid leukemia (AML) and to contribute to survival and proliferation of these cells. Of the 8 distinct mammalian isoforms of PI3K, it is the class I PI3Ks (p110alpha, p110beta, p110gamma, and p110delta) that are responsible for Akt activation. It is not known which PI3K isoform is critical in AML. Here we show that the p110delta isoform of PI3K is consistently expressed at a high level in blast cells from AML, in contrast to the other class I isoforms, the expression of which was very variable among patients. IC87114, a p110delta-selective inhibitor, suppressed both constitutive and Flt-3-stimulated Akt activation in blasts to the same extent as Ly294002, an inhibitor of all PI3K isoforms. Moreover, IC87114 inhibited AML cell proliferation without affecting the proliferation of normal hematopoietic progenitor cells. These observations identify p110delta as a potential therapeutic target in AML.
authors.affiliation: Service d'Hématologie, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sujobert
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardet
authors.forename: Pascale
authors.initials: P
authors.lastname: Cornillet-Lefebvre
authors.forename: Joel S
authors.initials: JS
authors.lastname: Hayflick
authors.forename: Nolwen
authors.initials: N
authors.lastname: Prie
authors.forename: Frederic
authors.initials: F
authors.lastname: Verdier
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Odile
authors.initials: O
authors.lastname: Muller
authors.forename: Florence
authors.initials: F
authors.lastname: Pesce
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: Mathilde
authors.initials: M
authors.lastname: Hunault-Berger
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
authors.forename: Bruno
authors.initials: B
authors.lastname: Villemagne
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.forename: Bruno
authors.initials: B
authors.lastname: Audhuy
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Brigitte
authors.initials: B
authors.lastname: Witz
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Chantal
authors.initials: C
authors.lastname: Himberlin
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.forename: Bruno
authors.initials: B
authors.lastname: Lioure
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Cahn
authors.forename: Francois
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007527:Isoenzymes; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C497132:PIK3CB protein, human; C486018:PIK3CD protein, human; C421683:Pik3cd protein, mouse; C494918:AKT1 protein, human