Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
Br J Haematol. 2023 Sep;202(6):1178-1191. doi: 10.1111/bjh.18983. Epub 2023 Jul 19.
Although tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukaemia (CML), TKI resistance remains a major challenge. Here, we demonstrated that plant homeodomain finger protein 8 (PHF8), a histone demethylase was aberrantly enriched in CML samples compared to healthy controls. PHF8 inhibited CML cell differentiation and promoted CML cell proliferation. Furthermore, the proliferation-inhibited function of PHF8-knockdown have stronger effect on imatinib mesylate (IM)-resistant CML cells. Mechanistically, we identified that PHF8 as a transcriptional modulator interacted with the promoter of the BCR::ABL1 fusion gene and alters the methylation levels of H3K9me1, H3K9me2 and H3K27me1, thereby promoting BCR::ABL1 transcription. Overall, our study suggests that targeting PHF8, which directly regulates BCR::ABL1 expression, is a useful therapeutic approach for CML.
虽然酪氨酸激酶抑制剂（TKI）已经彻底改变了慢性髓性白血病（CML）的治疗方法，但 TKI 耐药仍然是一个主要挑战。在这里，我们证明与健康对照相比，组蛋白去甲基化酶植物同源结构域指蛋白 8（PHF8）在 CML 样本中异常富集。PHF8 抑制 CML 细胞分化并促进 CML 细胞增殖。此外，PHF8 敲低的增殖抑制功能对甲磺酸伊马替尼（IM）耐药 CML 细胞的作用更强。从机制上讲，我们确定 PHF8 作为转录调节剂与 BCR::ABL1 融合基因的启动子相互作用，并改变 H3K9me1、H3K9me2 和 H3K27me1 的甲基化水平，从而促进 BCR::ABL1 转录。总的来说，我们的研究表明，靶向直接调节 BCR::ABL1 表达的 PHF8 是治疗 CML 的一种有效方法。
