Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia.
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.
Sujobert
Pierre
P
Service d'Hématologie, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.
Bardet
Valerie
V
Cornillet-Lefebvre
Pascale
P
Hayflick
Joel S
JS
Prie
Nolwen
N
Verdier
Frederic
F
Vanhaesebroeck
Bart
B
Muller
Odile
O
Pesce
Florence
F
Ifrah
Norbert
N
Hunault-Berger
Mathilde
M
Berthou
Christian
C
Villemagne
Bruno
B
Jourdan
Eric
E
Audhuy
Bruno
B
Solary
Eric
E
Witz
Brigitte
B
Harousseau
Jean Luc
JL
Himberlin
Chantal
C
Lamy
Thierry
T
Lioure
Bruno
B
Cahn
Jean Yves
JY
Dreyfus
Francois
F
Mayeux
Patrick
P
Lacombe
Catherine
C
Bouscary
Didier
D
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
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