title: 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.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore 169857.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.forename: Tzuen Yih
authors.initials: TY
authors.lastname: Saw
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Janes
authors.forename: Kassoum
authors.initials: K
authors.lastname: Nacro
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: An Qi
authors.initials: AQ
authors.lastname: Lim
authors.forename: Chia-Tien
authors.initials: CT
authors.lastname: Chang
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.forename: Hung
authors.initials: H
authors.lastname: Fan
authors.forename: Charles T H
authors.initials: CT
authors.lastname: Chuah
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001752:Blast Crisis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D051176:beta Catenin; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Wnt pathway; biomarker; cancer stem cell; xenograft