KLF4 Represses DYRK2 Inhibition of Self-renewal and Survival Through c-Myc and p53 in Leukemia Stem/Progenitor Cells

Leukemiastem cells are a rare population with a primitive progenitorphenotype that can initiate, sustain, and recapitulate leukemiathrough a poorly understood mechanism of self-renewal. Here, we report that KLF4promotes disease progression in a murine model of chronic myeloid leukemia(CML)-like myeloproliferative neoplasia by repressing an inhibitory mechanism of preservation in leukemiastem/ progenitor cellswith leukemia-initiating capacity. Deletion of the Klf4gene severely abrogated the maintenance of BCR-ABL1(p210)-induced CML by impairing survival and self-renewal in BCR-ABL1+ CD150+ LSK leukemic cells. Mechanistically, KLF4repressed the Dyrk2 gene in leukemic stem/ progenitor cells; thus, loss of KLF4resulted in elevated levels of DYRK2 kinase, 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 SIAH2with vitamin K3promoted apoptosis and abrogated self-renewal in murine and human CML stem/ progenitor cells. Altogether, our results suggest that DYRK2 is a molecular checkpoint controlling both 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.