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ABSTRACT
Objectives: Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. The aim of the study was to compare constitutive PI3K-Akt-mTOR activation of primary AML cells for a large group of unselected patients.
Methods: We investigated expression and phosphorylation of 18 mediators in the PI3K-Akt-mTOR main track by flow cytometry for AML cells derived from 77 patients, and compared this with global gene expression profiles, proteomic, and transcriptomic profiles, and susceptibility to antileukemic agents.
Results: Patients were divided into two main subsets showing generally high or low constitutive pathway activation. The high activation subset was characterized by decreased frequency of cells showing monocytic differentiation, increased frequency of adverse karyotypes, decreased constitutive cytokine release, and increased expression of certain integrins. Finally, the two groups differed in their expression of genes encoding regulators of protein phosphorylation, whereas phosphoproteomic analyses showed differences especially with regard to transcriptional regulation. Antiproliferative effects of pathway inhibition were generally stronger for the low phosphorylation subset.
Conclusion: The constitutive PI3K-Akt-mTOR activation differed between patients; this difference appears to be a part of complex phenotypic differences including cell communication, intracellular signaling through other pathways, and transcriptional regulation.
Author contributions
IN was responsible for all flow-cytometric analyses, analysis and presentation of results, writing of the manuscript; KJH supervised flow-cytometric studies, analysis of flow-cytometric data, presentation of results and writing of manuscript; AKB, pharmacological (pathway inhibitors) and cytokine release studies; FB, FS, EA and MH-V, responsible for the proteomic and phosphoproteomic analyses; SB-B, responsible for the cytarabine experiments; BTG and JS contributed to the flow-cytometric methodology; HR, responsible for global gene expression studies, writing of the final manuscript; ØB, designed the study, responsible for the biobank, interpretation and presentation of results, writing of the manuscript.
Acknowledgment
The technical assistance of Kristin P. Rye, Karen Marie Hagen and Randi Hovland is gratefully acknowledged.
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplemental data
Supplemental data for this article can be accessed here.
