Li Xuexiao, Wang Luping, Qin Xun, Chen Xiaohui, Li Li, Huang Zhibin, Zhang Wenqing, Liu Wei
Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510006, People's Republic of China.
Department of Coloproctology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510006, People's Republic of China.
Cell Death Discov. 2022 Jul 16;8(1):323. doi: 10.1038/s41420-022-01121-2.
Myelodysplastic syndromes (MDS) are characterized by daunting genetic heterogeneity and a high risk of leukemic transformation, which presents great challenges for clinical treatment. To identify new chemicals for MDS, we screened a panel of FDA-approved drugs and verified the neutrophil hyperplasia inhibiting role of 17β-estradiol (E2, a natural estrogen) in several zebrafish MDS models (pu.1, irf8 and c-myb). However, the protective mechanism of estrogen in the development of hematological malignancies remains to be explored. Here, analyzing the role of E2 in the development of each hematopoietic lineage, we found that E2 exhibited a specific neutrophil inhibiting function. This neutrophil inhibitory function of E2 is attributed to its down-regulation of c-myb, which leads to accelerated apoptosis and decreased proliferation of neutrophils. We further showed that knockdown of hif1α could mimic the neutrophil inhibiting role of E2, and hif1α overexpression could reverse the protective function of E2. Collectively, our findings highlight the protective role of E2 on MDS by inhibiting hif1α-c-myb pathway, suggesting that E2 is a promising and effective drug for hematopoietic tumors associated with abnormal neutrophil hyperplasia.
骨髓增生异常综合征（MDS）具有令人畏惧的基因异质性和白血病转化的高风险，这给临床治疗带来了巨大挑战。为了鉴定用于MDS的新化学物质，我们筛选了一组美国食品药品监督管理局（FDA）批准的药物，并在几种斑马鱼MDS模型（pu.1、irf8和c-myb）中验证了17β-雌二醇（E2，一种天然雌激素）对中性粒细胞增生的抑制作用。然而，雌激素在血液系统恶性肿瘤发生发展中的保护机制仍有待探索。在此，通过分析E2在各造血谱系发育中的作用，我们发现E2具有特定的中性粒细胞抑制功能。E2的这种中性粒细胞抑制功能归因于其对c-myb的下调，这导致中性粒细胞凋亡加速和增殖减少。我们进一步表明，敲低hif1α可模拟E2的中性粒细胞抑制作用，而hif1α过表达可逆转E2的保护功能。总体而言，我们的研究结果突出了E2通过抑制hif1α-c-myb途径对MDS的保护作用，表明E2是一种用于与异常中性粒细胞增生相关的造血肿瘤的有前景且有效的药物。
