The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway mediates diverse and important physiological cell functions which include proliferation, differentiation, survival, motility, autophagy, and metabolism. However, dysregulated PI3K/Akt/mTOR signaling has been documented in a wide range of neoplasias, including malignant hematological disorders. It is now emerging that this signaling network plays a key role during normal hematopoiesis, a tightly regulated process resulting in the formation of all blood lineages. Blood cell development encompasses a complex series of events which are mainly regulated by actions of cytokines, a family of extracellular ligands which stimulate many biological responses in a wide array of cell types. Hematopoiesis is strictly dependent on the correct function of the bone marrow microenvironment (BMM), as BMM cells secrete most of the cytokines. Several of these cytokines activate the PI3K/Akt/mTOR signaling network and regulate proliferation, survival, and differentiation events during hematopoiesis. Here, we review the evidence that links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of hematopoietic stem cells and the process of myelopoiesis, including lineage commitment. We then highlight the emerging role played by aberrant PI3K/Akt/mTOR signaling during leukemogenesis.

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…Moreover, the expression of three proteins known to be regulated at the translation initiation level, MCL-1, Survivin and CDK-2, 29 was markedly reduced in Jurkat cells after 24 h of exposure to either PP-242 or OSI-027, but not to rapamycin (Figure 3e). Overall, these findings demonstrated that active site mTOR inhibitors are potent Lysates were clarified by centrifugation, and supernatants were incubated with 7 methyl-GTP-Sepharose beads in 400 ml binding buffer.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…[76][77][78][79][80][81] However, more recent investigations did not confirm these findings. [76][77][78][79][80][81] Nevertheless, Akt also phosphorylates proline-rich Akt-substrate-40 (PRAS40), an inhibitor of mTORC1, and by doing so, it prevents the ability of PRAS40 to suppress mTORC1 signaling (recently reviewed in refs. 2,[79][80][81] ).…”

“…[76][77][78][79][80][81] Nevertheless, Akt also phosphorylates proline-rich Akt-substrate-40 (PRAS40), an inhibitor of mTORC1, and by doing so, it prevents the ability of PRAS40 to suppress mTORC1 signaling (recently reviewed in refs. 2,[79][80][81] ). Thus, this could be yet another mechanism by which Akt activates mTORC1.…”

“…Moreover, PRAS40 is a substrate of mTORC1 itself, and it has been shown that mTORC1-mediated phosphorylation of PRAS40 facilitates the removal of its inhibition on downstream signaling of mTORC1. 2,[79][80][81] The relationship between Akt and mTOR is further complicated by the existence of mTORC2, which in some cell types, displays rapamycin-insensitive activity. 76 Akt and mTOR are linked to each other via positive and negative regulatory circuits, which restrain their simultaneous hyperactivation through a mechanism involving p70 S6K and PI3K.…”

“…Other factors such as eIF4B and eIF4H aid in the recruitment of ribosomes to the complex by stimulating the helicase activity of eIF4A. 2,[79][80][81] Poly A binding protein may also be involved in assembly to the complex. 4E binding protein-1 acts to inhibit the assembly of the translation complex.…”