PI3K/AKT pathway activation in acute myeloid leukaemias is not associated with AKT1 pleckstrin homology domain mutation

Abstract

SummaryDespite its' central role, the precise mechanisms of the phosphoinositide 3-kinase/Akt (PI3K)/Akt pathway activation in acute myeloid leukaemia (AML) have not been elucidated. Recently, a recurrent novel AKT1 pleckstrin homology domain (PHD) mutation leading to membrane translocation, constitutive AKT activation and leukaemia development in mice was described. To assess AKT1 PHD mutations in AML, we sequenced 57 specimens from 49 AML patients, all of whom showed PI3K/AKT pathway activation by analysis of total and phospho-protein expression for AKT, mTor, p70S6Kinase, S6ribosomal protein and PTEN. No mutations in AKT1 PHD were identified, making this mutation an unlikely cause of PI3K/ AKT pathway activation in AML.

The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia

“…Overall, it is conceivable that deregulation of the PI3K/Akt pathway in AML relates to phosphatase defects as no activating mutations of PI3K or Akt have been shown to date. 15,16,18,19 In our study, the level of phosphorylation on Thr308 was a strong prognostic factor for OS, EFS and RFS, butFin contrast with earlier studiesFSer473 was not associated with either a poor or a favourable prognosis. 5,7 In non-small-cell lung cancer, it has also been reported that Thr308, but not Ser473, has prognostic value.…”

“…Antibodies were obtained from Cell Signalling (Beverly, MA, USA): phospho-Akt Thr308, phospho-Akt Ser473, PTEN, phospho-PTEN Ser380/ Thr382/383, anti-PP2A catalytic subunit (PP2Ac), phospho-FOXO3A (Thr32), phospho-GSK3b (Ser21/9) and GSK3b. [17][18][19][20] if 45% marrow blasts persisted on day 15. Complete response patients with an HLA-identical sibling received an allograft (directly if they were p50 years of age; after consolidation and reducedintensity conditioning if they were X51-year-old).…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…The PI3K pathway seems to be activated in AML, but thus far, no mutations of PTEN or other components such as AKT have been found in AML (Tibes et al, 2008). Upregulation of PI3K activity contributes to malignant alterations in proliferation, survival, metabolism, migration and membrane trafficking (Tamguney and Stokoe, 2007).…”

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…Cells with this AKT1 mutation have not been observed to have mutations at PI3K; a similar scenario is also frequently observed with RAS and BRAF mutations. 282 The AKT1 mutation alters the electrostatic interactions of AKT1 that allows it to form new hydrogen bonds with the natural phosphoinositol ligand. 281 The PH domain mutation confers many different properties to the AKT1 gene.…”

“…281 In a relatively small cohort of AML patients, such a mutation was not found. 282 It will be important to determine if this AKT1 mutation (E17K) is also present in leukemias.…”