A KLF4-DYRK2–mediated pathway regulating self-renewal in CML stem cells

• Published in: Blood 2019-11, Vol.134 (22), p.1960-1972
• Main Authors: Park, Chun Shik, Lewis, Andrew H., Chen, Taylor J., Bridges, Cory S., Shen, Ye, Suppipat, Koramit, Puppi, Monica, Tomolonis, Julie A., Pang, Paul D., Mistretta, Toni-Ann, Ma, Leyuan, Green, Michael R., Rau, Rachel, Lacorazza, H. Daniel
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - drug effects; Cell Survival - genetics; Dyrk Kinases; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene Deletion; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Mice; Mice, Knockout; Myeloid Neoplasia; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Vitamin K 3 - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2018875922

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. •Loss of KLF4 impairs self-renewal and survival in CML stem/progenitor cells through derepression of the DYRK2 gene.•Stabilization of DYRK2 protein inhibits survival and self-renewal in leukemia stem/progenitor cells via c-Myc depletion and p53 activation. [Display omitted]