Steroid resistance in Diamond Blackfan anemia associates with p57Kip2 dysregulation in erythroid progenitors.
Adult
Anemia, Diamond-Blackfan
/ drug therapy
Antigens, CD
/ metabolism
Cyclin-Dependent Kinase Inhibitor p27
/ biosynthesis
Cyclin-Dependent Kinase Inhibitor p57
/ biosynthesis
Dexamethasone
/ pharmacology
Drug Resistance
/ drug effects
Erythroid Precursor Cells
/ metabolism
Female
Humans
Male
Up-Regulation
/ drug effects
Bone marrow differentiation
Cell cycle
Development
Hematology
Hematopoietic stem cells
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
received:
21
08
2019
accepted:
14
01
2020
pubmed:
22
1
2020
medline:
31
12
2020
entrez:
22
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31961825
pii: 132284
doi: 10.1172/JCI132284
pmc: PMC7108903
doi:
pii:
Substances chimiques
Antigens, CD
0
CDKN1B protein, human
0
CDKN1C protein, human
0
Cyclin-Dependent Kinase Inhibitor p57
0
Cyclin-Dependent Kinase Inhibitor p27
147604-94-2
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2097-2110Subventions
Organisme : NHLBI NIH HHS
ID : U01 HL134812
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210986
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK032094
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210979
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214125
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144436
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL079571
Pays : United States
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