Steroid resistance in Diamond Blackfan anemia associates with [p57.sup.Kip2] dysregulation in erythroid progenitors

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 dev...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-04, Vol.130 (4), p.2097
Main Authors: Ashley, Ryan J, Yan, Hongxia, Wang, Nan, Hale, John, Dulmovits, Brian M, Papoin, Julien, Olive, Meagan E, Udeshi, Namrata D, Carr, Steven A, Vlachos, Adrianna, Lipton, Jeffrey M, Da Costa, Lydie, Hillyer, Christopher, Kinet, Sandrina, Taylor, Naomi, Mohandas, Narla, Narla, Anupama, Blanc, Lionel
Format: Article
Language:English
Subjects:
Analysis
Anemia
Central nervous system depressants
Dexamethasone
Glucocorticoids
Proteins
Proteomics
Scientific equipment industry
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Summary: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.sup.+] progenitor cells, specifically increasing the expansion of [CD34.sup.+] progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, [CD34.sup.+] progenitors resulted in the expansion of a newly defined [CD34.sup.+][CD36.sup.+] [CD71.sup.hi] [CD105.sup.med] 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 [p57.sup.Kip2], a Cip/Kip cyclin-dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of [p57.sup.Kip2], but not the related [p57.sup.Kip1], 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 [p57.sup.Kip2] 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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI132284