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 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+ LSK leukemic cells. Mechanistically, KLF4 repressed the Dyrk2 gene in leukemic stem/progenitor cells; thus, loss of KLF4 resulted 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 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 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.

中文翻译：

---

KLF4 通过 c-Myc 和 p53 抑制 DYRK2 对白血病干细胞/祖细胞自我更新和生存的抑制


白血病干细胞是一种罕见的群体，具有原始祖细胞表型，可以通过一种知之甚少的自我更新机制启动、维持和重现白血病。在此，我们报告KLF4通过抑制具有白血病起始能力的白血病干细胞/祖细胞的保存抑制机制，促进慢性粒细胞白血病（CML）样骨髓增殖性肿瘤小鼠模型的疾病进展。 Klf4 基因的缺失会损害 BCR-ABL1+ CD150+ LSK 白血病细胞的存活和自我更新，从而严重破坏 BCR-ABL1(p210) 诱导的 CML 的维持。从机制上讲，KLF4 抑制白血病干细胞/祖细胞中的 Dyrk2 基因；因此，KLF4 的缺失导致 DYRK2 激酶水平升高，这与通过消耗 c-Myc 蛋白和 p53 激活来抑制生存和自我更新有关。除了转录调节之外，通过用维生素 K3 抑制泛素 E3 连接酶 SIAH2 来稳定 DYRK2 蛋白，可促进小鼠和人类 CML 干/祖细胞的细胞凋亡并消除自我更新。总而言之，我们的结果表明，DYRK2 是一个分子检查点，控制着 CML 细胞中 p53 和 c-Myc 介导的生存和自我更新调节，具有可以用小分子靶向的白血病起始能力。