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The glucocorticoid receptor elicited proliferative response in human erythropoiesis is BCL11A-dependent.
Mazzarini, Maria; Cherone, Jennifer; Nguyen, Truong; Martelli, Fabrizio; Varricchio, Lilian; Funnell, Alister P W; Papayannopoulou, Thalia; Migliaccio, Anna Rita.
Afiliação
  • Mazzarini M; Department of Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, Italy.
  • Cherone J; Altius Institute for Biomedical Sciences, Seattle, WA, USA.
  • Nguyen T; Altius Institute for Biomedical Sciences, Seattle, WA, USA.
  • Martelli F; Altius Institute for Biomedical Sciences, Seattle, WA, USA.
  • Varricchio L; National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
  • Funnell APW; Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Papayannopoulou T; Altius Institute for Biomedical Sciences, Seattle, WA, USA.
  • Migliaccio AR; Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA.
Stem Cells ; 2024 Aug 07.
Article em En | MEDLINE | ID: mdl-39110040
ABSTRACT
Prior evidence indicates that the erythroid cellular response to glucocorticoids (GC) has developmental specificity, namely, that developmentally more advanced cells that are undergoing or have undergone fetal to adult globin switching are more responsive to GC-induced expansion. To investigate the molecular underpinnings of this, we focused on the major developmental globin regulator BCL11A. We compared a) levels of expression and nuclear content of BCL11A in adult erythroid cells upon GC stimulation; b) response to GC of CD34+ cells from patients with BCL11A microdeletions and reduced BCL11A expression, and; c) response to GC of two cellular models (HUDEP-2 and adult CD34+ cells) before and after reduction of BCL11A expression by shRNA. We observed that a) GC-expanded erythroid cells from a large cohort of blood donors displayed amplified expression and nuclear accumulation of BCL11A; b) CD34+ cells from BCL11A microdeletion patients generated fewer erythroid cells when cultured with GC compared to their parents, while the erythroid expansion of the patients was similar to that of their parents in cultures without GC, and; c) adult CD34+ cells and HUDEP-2 cells with shRNA-depleted expression of BCL11A exhibit reduced expansion in response to GC. In addition, RNA-seq profiling of shRNA-BCL11A CD34+ cells cultured with and without GC was similar (very few differentially expressed genes), while GC-specific responses (differential expression of GILZ and of numerous additional genes) were observed only in controls cells with unperturbed BCL11A expression. These data indicate that BCL11A is an important participant of certain aspects of the stress pathway sustained by GC.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article