Department of Molecular Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, Hempstead, New York, USA.
Center for Autoimmunity, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.
J Clin Invest. 2020 Apr 1;130(4):2097-2110. doi: 10.1172/JCI132284.
Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanisms through which glucocorticoids regulate human erythropoiesis remain poorly understood. We report that the sensitivity of erythroid differentiation to dexamethasone is dependent on the developmental origin of human CD34+ progenitor cells, specifically increasing the expansion of CD34+ progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, CD34+ progenitors resulted in the expansion of a newly defined CD34+CD36+CD71hiCD105med immature colony-forming unit-erythroid (CFU-E) population. Furthermore, proteomics analyses revealed the induction of distinct proteins in dexamethasone-treated PB and CB erythroid progenitors. Dexamethasone treatment of PB progenitors resulted in the specific upregulation of p57Kip2, a Cip/Kip cyclin-dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of p57Kip2, but not the related p27Kip1, significantly attenuated the impact of dexamethasone on erythroid differentiation and inhibited the expansion of the immature CFU-E subset. Notably, in the context of DBA, we found that steroid resistance was associated with dysregulated p57Kip2 expression. Altogether, these data identify a unique glucocorticoid-responsive human erythroid progenitor and provide new insights into glucocorticoid-based therapeutic strategies for the treatment of patients with DBA.
尽管类固醇在治疗 Diamond Blackfan 贫血（DBA）方面具有有效的临床应用，但糖皮质激素调节人类红细胞生成的机制仍知之甚少。我们报告说，红细胞分化对地塞米松的敏感性取决于人类 CD34+祖细胞的发育起源，具体来说，它增加了外周血（PB）而不是脐带血（CB）中 CD34+祖细胞的扩增。地塞米松处理红细胞分化的 PB，但不是 CB，CD34+祖细胞导致新定义的 CD34+CD36+CD71hiCD105med 未成熟集落形成单位-红细胞（CFU-E）群体的扩增。此外，蛋白质组学分析显示，地塞米松处理的 PB 和 CB 红细胞祖细胞中诱导了不同的蛋白质。地塞米松处理 PB 祖细胞导致细胞周期蛋白依赖性激酶抑制剂 p57Kip2 的特异性上调，我们确定这种诱导是关键的；shRNA 介导的 p57Kip2 下调，但不是相关的 p27Kip1 下调，显著减弱了地塞米松对红细胞分化的影响，并抑制了未成熟 CFU-E 亚群的扩增。值得注意的是，在 DBA 的情况下，我们发现类固醇耐药与 p57Kip2 表达失调有关。总之，这些数据确定了一种独特的糖皮质激素反应性人类红细胞祖细胞，并为基于糖皮质激素的治疗策略治疗 DBA 患者提供了新的见解。
