Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia

Park, Sophie; Chapuis, Nicolas; Tamburini, Jérôme; Bardet, Valérie; Cornillet‐Lefèbvre, Pascale; Willems, Lise; Green, Alexa S.; Mayeux, Patrick; Lacombe, Catherine; Bouscary, Didier

doi:10.3324/haematol.2009.013797

Cited by 258 publications

(224 citation statements)

References 112 publications

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“…Thus, targeting mTOR more globally is becoming an important therapeutic option in AML therapy. 139,[143][144][145][146][147] Studies by other investigators performing high-throughput screening assays have identified 4EGI-1, which is a 4E-BP1 mimetic and a potent inhibitor of the interactions between eIF4E and eIF4G. The inhibitor 4EGI-1 has been shown in some systems to inhibit the growth of BCR-ABL-transformed Ba/F3 hematopoietic cells, but not the parental interleukin-3-dependent cells line (Ba/F3).…”

Section: Pi3k/pten/akt/mtor Drug Resistance and Leukemia Therapymentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Pi3k/pten/akt/mtor Drug Resistance and Leukemia Therapymentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…The phosphoinositol 3-kinase (PI3K)/AKT pathway is frequently activated in AML, [16][17][18] and it is known that NAMPT induces AKT phosphorylation. 19,20 We did not detect any changes in the levels of phospho-PI3K p85 (Tyr 458) or expression of total PI3K p85 protein in HL-60 cells treated with FK866 or AC93253 compared to DMSO-treated control cells (Online Supplementary Figure S2).…”

Section: Inhibition Of Nampt or Sirtuin 2 Inactivates Akt And Activatmentioning

confidence: 99%

“…[13][14][15] The AKT pathway is frequently activated in acute myeloid leukemia (AML). [16][17][18] However, the mechanisms leading to AKT activation in AML are not completely clear. NAMPT (visfatin) has recently been shown to induce AKT phosphorylation in endothelial cells and in cardiac fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundInhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear. Design and MethodsHere, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process. ResultsWe identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation. ConclusionsOur results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.

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“…In this sense, constitutive activation of the class I-A phosphoinositide3-kinase/serine-threonine kinase (PI3K/Akt) pathway, as the result of autocrine insulin-like growth factor-1 (IGF-1) receptor signaling, occurs in up to 50-80% of AML patients. 10,11 This PI3K/Akt up-regulation leads to over-expression of several downstream substrates increasing blast cell proliferation. [12][13][14] It has been reported that granulocytemacrophage colony-stimulating factor exerts anti-apoptotic ©2013 Ferrata Storti Foundation.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3and proliferative effects partially by increasing survivin levels through PI3K activation in AML. 15 Additionally, it has been shown in a mouse model that internal tandem duplication of Flt-3 regulates survivin expression via PI3K/Akt leading to aberrant progenitor cell proliferation. 16 Although the importance of the PI3K/Akt/survivin pathway has been reported in lung and colon cancer, 17,18 its incidence and prognostic impact in AML have not been described.In this study we analyzed the subcellular compartment distribution of WT survivin and the splicing variants survivin-2B and survivin-Delta-Ex3 in AML patients, the correlation with PI3K/Akt pathway activation, and the possible impact on outcome. MethodsWe included 105 consecutive patients diagnosed with AML between February 2006 and October 2010 in our institution. These patients' clinical features, biological characteristics and outcomes are listed in Table 1. Conventional cytogenetic investigations, fluorescence in situ hybridization and molecular studies for NPM1 mutations and FLT3-ITD were performed as previously described.19 Seventy-five patients suitable for intensive treatment received chemotherapy induction regimens based on PETHEMA Spanish Cooperative group protocols. Samples had been acquired during routine diagnostic assessments and were analyzed in accordance with the regulations and protocols approved by the "Reina Sofia" University Hospital. Informed consent had been obtained in accordance with the Declaration of Helsinki. For in vitro experiments, K562, HL-60 and MV4-11 leukemia cell lines were used (purchased from American Tissue Cell Culture, ATCC). Preparation of cytosolic and nuclear protein extractsCytosolic, membrane and nuclear proteins were sequentially isolated from mononuclear cells from bone marrow aspirates obtained at diagnosis, using a Q-proteome Cell Compartment kit (Qiagen Iberia SL, Madrid, Spain) according to the manufacture's instructions. Western blottingWT survivin and splicing variants were clearly distinguished by their different molecular weights: 16.5 KDa for the WT protein, 18 KDa for the 2B variant and 14 KDa for the Delta-Ex3 variant. The specificity of each isoform was further confirmed by blocking peptide experiments (Online Supplementary Figure S1). Cytosolic and nuclear specific fractions were tested for purity using anti-β actin (1:1000, Cell Signaling) and lamin-A (H-102, 1:500; Santa Cruz Biotechnology, Santa Cruz, CA, USA) (Online Supplementary Figure S2). Proteins were detected by chemiluminescence using a Chemigenius-2 device and quantified using Gene-Tools 5 analysis software (both from Syngene, Cambridge, UK) using β-actin or laminin as the loading control for cytoplasmic and nuclear extracts, respectively. Analysis of G0 quiescent and cell cycleFresh leukemic cells were first stained with fluorescein isothio-J. Serrano-López et al. 1878 haematologica | 2013; 98(12) Statistical analysisNormalized values of WT survivin and isoforms were...

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Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia

Cited by 258 publications

References 112 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

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