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|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|
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