Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis
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...
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MDPI AG
2018-09-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/9/332 |
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| author | Ina Nepstad Kimberley Joanne Hatfield Tor Henrik Anderson Tvedt Håkon Reikvam Øystein Bruserud |
| author_facet | Ina Nepstad Kimberley Joanne Hatfield Tor Henrik Anderson Tvedt Håkon Reikvam Øystein Bruserud |
| author_sort | Ina Nepstad |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T09:21:48Z |
| format | Article |
| id | doaj.art-fdeb8c2c4fba46f0b62593a7bfb4d47c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:21:48Z |
| publishDate | 2018-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fdeb8c2c4fba46f0b62593a7bfb4d47c2023-09-02T14:30:26ZengMDPI AGCancers2072-66942018-09-0110933210.3390/cancers10090332cancers10090332Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse PrognosisIna Nepstad0Kimberley Joanne Hatfield1Tor Henrik Anderson Tvedt2Håkon Reikvam3Øystein Bruserud4Section for Hematology, Department of Clinical Science, University of Bergen, 5021 Bergen, NorwaySection for Hematology, Department of Clinical Science, University of Bergen, 5021 Bergen, NorwaySection for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, NorwaySection for Hematology, Department of Clinical Science, University of Bergen, 5021 Bergen, NorwaySection for Hematology, Department of Clinical Science, University of Bergen, 5021 Bergen, NorwayClonal 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.http://www.mdpi.com/2072-6694/10/9/332acute myeloid leukemiaPI3KAktmTORphosphorylationclonal heterogeneity |
| spellingShingle | Ina Nepstad Kimberley Joanne Hatfield Tor Henrik Anderson Tvedt Håkon Reikvam Øystein Bruserud Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis Cancers acute myeloid leukemia PI3K Akt mTOR phosphorylation clonal heterogeneity |
| title | Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis |
| title_full | Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis |
| title_fullStr | Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis |
| title_full_unstemmed | Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis |
| title_short | Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis |
| title_sort | clonal heterogeneity reflected by pi3k akt mtor signaling in human acute myeloid leukemia cells and its association with adverse prognosis |
| topic | acute myeloid leukemia PI3K Akt mTOR phosphorylation clonal heterogeneity |
| url | http://www.mdpi.com/2072-6694/10/9/332 |
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