Estrogens revert neutrophil hyperplasia by inhibiting Hif1α-cMyb pathway in zebrafish myelodysplastic syndromes models

Abstract

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.1G242D/G242D, irf8Δ57Δ/57 and c-mybhyper). 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.