期刊
BLOOD
卷 134, 期 22, 页码 1960-1972出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2018875922
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资金
- Rally Foundation for Childhood Cancer Research
- Gabrielle's Angel Foundation for Cancer Research
- Cancer Prevention Research Institute of Texas [RP140179]
- National Cancer Institute, National Institutes of Health [R01 CA207086-01A1]
- National Institute of General Medical Sciences T32, National Institutes of Health [GM008231]
- Baylor College of Medicine Comprehensive Cancer Training Program from the Cancer Prevention and Research Institute of Texas [RP160283]
- Cytometry and Cell Sorting Core at Baylor College of Medicine [P30 AI036211, P30 CA125123, S10 RR024574]
- Flow Cytometry Core at Texas Children's Cancer and Hematology Center [S10 OD020066]
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 Kruppel-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.
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