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Cancers 2018, 10(9), 332; https://doi.org/10.3390/cancers10090332

Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis

1
Section for Hematology, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
2
Departments of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway
3
Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
*
Author to whom correspondence should be addressed.
Received: 24 July 2018 / Revised: 5 September 2018 / Accepted: 13 September 2018 / Published: 14 September 2018
(This article belongs to the Special Issue Cancer Biomarkers)
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Abstract

Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML. View Full-Text
Keywords: acute myeloid leukemia; PI3K; Akt; mTOR; phosphorylation; clonal heterogeneity acute myeloid leukemia; PI3K; Akt; mTOR; phosphorylation; clonal heterogeneity
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Nepstad, I.; Hatfield, K.J.; Tvedt, T.H.A.; Reikvam, H.; Bruserud, Ø. Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis. Cancers 2018, 10, 332.

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