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

• DOI: 10.1073/pnas.1301838110
• Publication Date: 2013-06-05T05:30:32Z
• 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
• Keywords: 0301 basic medicine; Wnt pathway; 610; Bone Marrow Cells; Protein Serine-Threonine Kinases; Mice; 03 medical and health sciences; Mice, Inbred NOD; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Animals; Humans; Phosphorylation; RNA, Small Interfering; Protein Kinase Inhibitors; beta Catenin; Aniline Compounds; Cancer stem cell; Xenograft; Intracellular Signaling Peptides and Proteins; Biomarker; 540; Xenograft Model Antitumor Assays; Eukaryotic Initiation Factor-4E; Purines; Neoplastic Stem Cells; Female; Blast Crisis; K562 Cells

Significance Cancer stem cells (CSCs) frequently acquire the ability to self-renew and persist in their hosts by coopting normal stem cell programs. Blast crisis (BC) chronic myeloid leukemia is a prototypic example, as the acquired activation of β-catenin signaling that enables BC CSC function is also important in normal hematopoietic stem cell maintenance. In identifying eIF4E phosphorylation by the MNK kinases as a necessary step in β-catenin activation in BC CSCs, but not normal hematopoietic stem cells, we define a therapeutic target in BC. Our studies suggest that clinical trials with MNK kinase inhibitors are warranted in BC chronic myeloid leukemia.