Pharmacologic targeting of the PI3K/mTOR pathway controls release of angioregulators from primary human acute myeloid leukemia cells and their neighboring stromal cells
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Håkon Reikvam1,2, Ina Nepstad1, Øystein Bruserud1,2, Kimberley Joanne Hatfield1,2
1 Section for Hematology, Department of Clinical Science, University of Bergen, Norway
2 Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Øystein Bruserud, email:
Keywords: Acute myeloid leukemia, cytokines, mTOR, PI3K, Angiogenesis, Bone marrow microenvironment, Pharmacological intervention
Received: April 10, 2013, Accepted: May 10, 2013, Published: May 11, 2013
Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells.
Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects.
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