Please use this identifier to cite or link to this item:
|Title:||Targeting of the MNK-eIF4E axis in blast crisis Chronic myeloid leukemia inhibits leukemia stem cell function|
|Authors:||Lim, S. |
Cancer stem cell
|Citation:||Lim, S., Saw, T.Y., Zhang, M., Janes, M.R., Nacro, K., Hill, J., Lim, A.Q., Chang, C.-T., Fruman, D.A., Rizzieri, D.A., Tan, S.Y., Fan, H., Chuah, C.T.H., Ong, S.T. (2013-06-18). Targeting of the MNK-eIF4E axis in blast crisis Chronic myeloid leukemia inhibits leukemia stem cell function. Proceedings of the National Academy of Sciences of the United States of America 110 (25) : E2298-E2307. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.1301838110|
|Abstract:||Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated β-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSC s) and LSCs depend on β-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates β-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased β-catenin protein synthesis, whereas MNK-depen-dent eIF4E phosphorylation is required for nuclear translocation and activation of β-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, β-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.|
|Source Title:||Proceedings of the National Academy of Sciences of the United States of America|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Aug 16, 2018
WEB OF SCIENCETM
checked on Jul 23, 2018
checked on Jun 22, 2018
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.