BCL11A MEDIATES THE GLUCOCORTICOID RECEPTOR-DEPENDENT STRESS
RESPONSE IN HUMAN ERYTHROPOIESIS
Lilian Varricchio1, Eliza B. Geer2, Fabrizio Martelli3, Maria Mazzarini4, Alister Funnel5, Thalia
Papayannopoulou6, James Biker1 and Anna Rita Migliaccio4,7
(1)Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (ISMMS), New York
(2)Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center,
New York
(3)National Center for Preclinical and Clinical Research and Evaluation of Pharmaceutical Drugs,
Rome, Italy
(4)Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, Italy
(5)Department of Genome Sciences, University of Washington, Seattle
(6)University of Washington, Department of Medicine, Division of Medical Genetics, Seattle
(7)Myeloproliferative Neoplasm Research Consortium, New York
Extrapolations from data in mouse models and from human cells expanded ex vivo into
erythroid cells after supplementation with the GR agonist Dexamethazone , suggest that the
GR plays an important role in the regulation of stress erythropoiesis in man. However, the
mechanistic details of stress erythropoiesis are still poorly understood. By exploring the
effects of Dexa on erythroid expansion of CD34+ cells from a large number of normal adult
donors we documented that Dexa expands a population of immature erythroid cells and
directly activates BCL11A expression in these cells, with greater levels of BCL11A mostly in
their nuclei ,compared to cells without Dexa. Total globin was also increased with beta more
than gamma. These data suggested that BCL11A may be required for proper response to GR
activation. To test the validity of this hypothesis we have made observations in cells from
patients with BCL11A (microdeletion) deficiencies and from Cushing patients with gain of
function of GR-mediated erythrocytosis. We found that BCL11A-deficient CD34+ cells
generated lower numbers of maturing erythroid cells compared to controls with or without
Dexa addition ,suggesting a poor response to Dexa. In Cushing’s patients we found that their
CD34+ cells have the unique CD36+ (thrombospondin), CD110+ (MPL, the receptor for
thrombopoietin) and CD133+ (the hematopoietic stem cell marker prominin) phenotype. This
phenotype resembles that of CD34+ cells generated in vitro after 2-days of culture with
Dex (Heideveld et al., Haematologica.2015;100:1396). These progenitor cells generate
similarly large number of immature erythroid cells in culture with and without Dex. By
contrast with normal cells, these active cells also express lower levels of the cytoplasm-restricted
form of GRα (GRS203) and greater levels of GILZ than normal cells, The levels of
BCL11A and of γ-globin expressed by erythroid cells generated with and without Dex by
Cushing’s patient cells was similar, suggesting that nuclear activation of BCL11A expression
was part of the constitutive response to Dexa of these cells. Taken together our data expand
the biology of stress erythropoiesis and suggest that BCL11A is a target gene that mediates
the activity of this receptor for a stress response.
POSTER 9
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES