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Novel B55α-PP2A mutations in AML promote AKT T308 phosphorylation and sensitivity to AKT inhibitor-induced growth arrest
- Source :
- Oncotarget, vol 7, iss 38, Oncotarget
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- Activation of the Protein Kinase B (PKB), or AKT pathway has been shown to correlate with acute myeloid leukemia (AML) prognosis. B55α-Protein Phosphatase 2A (PP2A) has been shown to dephosphorylate AKT at Thr-308 rendering it inactive. In fact, low expression of the PP2A regulatory subunit B55α was associated with activated phospho-AKT and correlated with inferior outcomes in AML. Despite this fact, no studies have specifically demonstrated a mechanism whereby B55α expression is regulated in AML. In this study, we demonstrate novel loss of function mutations in the PPP2R2A gene identified in leukemic blasts from three AML patients. These mutations eliminate B55α protein expression thereby allowing constitutive AKT activation. In addition, leukemic blasts with PPP2R2A gene mutation were more sensitive to treatment with the AKT inhibitor MK2206, but less responsive to the PP2A activator FTY720. Using leukemia cell lines, we further demonstrate that B55α expression correlates with AKT Thr-308 phosphorylation and predicts responsiveness to AKT inhibition and PP2A activation. Together our data illustrate the importance of the B55α-PP2A-AKT pathway in leukemogenesis. Screening for disruptions in this pathway at initial AML diagnosis may predict response to targeted therapies against AKT and PP2A.
- Subjects :
- 0301 basic medicine
Myeloid
Gene mutation
0302 clinical medicine
Heterocyclic Compounds
hemic and lymphatic diseases
Akt Inhibitor MK2206
Medicine
Protein Phosphatase 2
Enzyme Inhibitors
Phosphorylation
Leukemic
Tumor
Leukemia
Gene Expression Regulation, Leukemic
Myeloid leukemia
Leukemia, Myeloid, Acute
B55 alpha
Oncology
030220 oncology & carcinogenesis
Heterocyclic Compounds, 3-Ring
Research Paper
Cell Survival
Oncology and Carcinogenesis
Acute
acute myeloid leukemia
3-Ring
Cell Line
Immunophenotyping
03 medical and health sciences
Cell Line, Tumor
Humans
Codon
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
business.industry
Activator (genetics)
Fingolimod Hydrochloride
AKT
protein phosphatase 2A
B55α
Protein phosphatase 2
030104 developmental biology
Gene Expression Regulation
Immunology
Mutation
Cancer research
protein kinase B
business
Proto-Oncogene Proteins c-akt
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Oncotarget, vol 7, iss 38, Oncotarget
- Accession number :
- edsair.doi.dedup.....6a42fc839fd55737ad91ae7666ed3389