1. A KLF4-DYRK2-mediated pathway regulating self-renewal in CML stem cells.
- Author
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Park CS, Lewis AH, Chen TJ, Bridges CS, Shen Y, Suppipat K, Puppi M, Tomolonis JA, Pang PD, Mistretta TA, Ma L, Green MR, Rau R, and Lacorazza HD
- Subjects
- Animals, Cell Survival drug effects, Cell Survival genetics, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Gene Deletion, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Mice, Knockout, Neoplastic Stem Cells pathology, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Vitamin K 3 pharmacology, Dyrk Kinases, Kruppel-Like Transcription Factors metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Neoplastic Stem Cells metabolism, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases metabolism, Signal Transduction
- Abstract
Leukemia stem cells are a rare population with a primitive progenitor phenotype that can initiate, sustain, and recapitulate leukemia through a poorly understood mechanism of self-renewal. Here, we report that Krüppel-like factor 4 (KLF4) promotes disease progression in a murine model of chronic myeloid leukemia (CML)-like myeloproliferative neoplasia by repressing an inhibitory mechanism of preservation in leukemia stem/progenitor cells with leukemia-initiating capacity. Deletion of the Klf4 gene severely abrogated the maintenance of BCR-ABL1(p210)-induced CML by impairing survival and self-renewal in BCR-ABL1+ CD150+ lineage-negative Sca-1+ c-Kit+ leukemic cells. Mechanistically, KLF4 repressed the Dyrk2 gene in leukemic stem/progenitor cells; thus, loss of KLF4 resulted in elevated levels of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2), which were associated with inhibition of survival and self-renewal via depletion of c-Myc protein and p53 activation. In addition to transcriptional regulation, stabilization of DYRK2 protein by inhibiting ubiquitin E3 ligase SIAH2 with vitamin K3 promoted apoptosis and abrogated self-renewal in murine and human CML stem/progenitor cells. Altogether, our results suggest that DYRK2 is a molecular checkpoint controlling p53- and c-Myc-mediated regulation of survival and self-renewal in CML cells with leukemic-initiating capacity that can be targeted with small molecules., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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