title: Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia.
abstract: The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110delta isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).
authors: Institut Cochin, Département d'Hématologie, CNRS, UMR8104, Paris.
authors: Sophie
authors: S
authors: Park
authors: Nicolas
authors: N
authors: Chapuis
authors: Jérôme
authors: J
authors: Tamburini
authors: Valérie
authors: V
authors: Bardet
authors: Pascale
authors: P
authors: Cornillet-Lefebvre
authors: Lise
authors: L
authors: Willems
authors: Alexa
authors: A
authors: Green
authors: Patrick
authors: P
authors: Mayeux
authors: Catherine
authors: C
authors: Lacombe
authors: Didier
authors: D
authors: Bouscary
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D016503:Drug Delivery Systems / Q000639:trends; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C486018:PIK3CD protein, human