Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34⁺ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.

中文翻译：

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前列腺素E1及其类似物米索前列醇通过EP4受体激活和抑制AP-1抑制人CML干细胞自我更新。

有效治疗慢性粒细胞性白血病（CML）很大程度上取决于消灭CML白血病干细胞（LSC）。我们最近表明，CML LSC依赖于Tcf1和Lef1因素进行自我更新。使用连接图，我们确定前列腺素E1（PGE1）是一个小分子，部分引起了由Tcf1 / Lef1缺乏引起的LSCs基因表达的变化。尽管它对正常的造血功能影响不大，但我们发现PGE1治疗损害了临床前鼠CML模型和移植CML患者CD34 ⁺的异种移植模型中LSC的持久性和活性。干/祖细胞。从机制上讲，PGE1作用于EP4受体并以β-catenin独立的方式抑制Fosb和Fos AP-1因子。米索前列醇是FDA批准的EP4激动剂，对CML具有类似的保护作用。这些发现表明，该PGE1-EP4途径的激活特别针对CML LSC，并且PGE1 / misoprostol与常规酪氨酸激酶抑制剂的组合可以为CML提供有效的治疗方法。