Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function.

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 (HSCs) 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-dependent 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.

• Authors: Sharon Lim, Tzuen Yih Saw, Min Zhang, Matthew R Janes, Kassoum Nacro, Jeffrey Hill, An Qi Lim, Chia-Tien Chang, David A Fruman, David A Rizzieri, Soo Yong Tan, Hung Fan, Charles T H Chuah, S Tiong Ong
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 25 Pg. E2298-307 (Jun 18 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23737503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• CGP 57380
• Eukaryotic Initiation Factor-4E
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Purines
• RNA, Small Interfering
• beta Catenin
• MKNK1 protein, human
• Protein Serine-Threonine Kinases

Topics

• Aniline Compounds (pharmacology)
• Animals
• Blast Crisis (drug therapy, metabolism, pathology)
• Bone Marrow Cells (metabolism, pathology)
• Eukaryotic Initiation Factor-4E (metabolism)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phosphorylation (physiology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Purines (pharmacology)
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)