Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F and A erythroblasts
- 27 May 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (22), 1957-1968
- https://doi.org/10.1182/blood.2020005058
Abstract
Reversing the developmental switch from fetal hemoglobin (HbF, alpha(2)gamma(2)) to adult hemoglobin (HbA, alpha(2)gamma(2)) is an important therapeutic approach in sickle cell disease (SCD) and beta-thalassemia. In healthy individuals, SCD patients, and patients treated with pharmacologic HbF inducers, HbF is present only in a subset of red blood cells known as F cells. Despite more than 50 years of observations, the cause for this heterocellular HbF expression pattern, even among genetically identical cells, remains unknown. Adult F cells might represent a reversion of a given cell to a fetal-like epigenetic and transcriptional state. Alternatively, isolated transcriptional or posttranscriptional events at the g-globin genes might underlie heterocellularity. Here, we set out to understand the heterogeneity of HbF activation by developing techniques to purify and profile differentiation stage-matched late erythroblast F cells and non-F cells (A cells) from the human HUDEP2 erythroid cell line and primary human erythroid cultures. Transcriptional and proteomic profiling of these cells demonstrated very few differences between F and A cells at the RNA level either under baseline conditions or after treatment with HbF inducers hydroxyurea or pomalidomide. Surprisingly, we did not find differences in expression of any known HbF regulators, including BCL11A or LRF, that would account for HbF activation. Our analysis shows that F erythroblasts are not significantly different from non-HbF-expressing cells and that the primary differences likely occur at the transcriptional level at the beta-globin locus.This publication has 71 references indexed in Scilit:
- Corepressor-dependent silencing of fetal hemoglobin expression by BCL11AProceedings of the National Academy of Sciences of the United States of America, 2013
- Establishment of Immortalized Human Erythroid Progenitor Cell Lines Able to Produce Enucleated Red Blood CellsPLOS ONE, 2013
- Combinatorial Assembly of Developmental Stage-Specific Enhancers Controls Gene Expression Programs during Human ErythropoiesisDevelopmental Cell, 2012
- Lin28b Reprograms Adult Bone Marrow Hematopoietic Progenitors to Mediate Fetal-Like LymphopoiesisScience, 2012
- A Functional Element Necessary for Fetal Hemoglobin SilencingThe New England Journal of Medicine, 2011
- Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell miceBlood, 2011
- Lin28 Mediates the Terminal Uridylation of let-7 Precursor MicroRNAMolecular Cell, 2008
- Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cellsJCI Insight, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Stimulation of F-Cell Production in Patients with Sickle-Cell Anemia Treated with Cytarabine or HydroxyureaThe New England Journal of Medicine, 1985