Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F and A-erythroblasts
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Reversing the developmental switch from fetal hemoglobin (HbF, α2γ2) to adult hemoglobin (HbA, α2β2) is an important therapeutic approach in sickle cell disease (SCD) and β-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 γ-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 β-globin locus.
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F-cells do not resemble fetal erythrocytes save for their high levels of HbF.
“F-cells do not resemble fetal erythrocytes save for their high levels of HbF.43”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [43]
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Pharmacogenomics of Hydroxyurea Therapy and Fetal Hemoglobin Levels in Sickle Cell Anemia
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p27Kip1 regulates γ-globin production
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CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease
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Variable cells with identical genetic codes
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- Authors
- Khandros, E., Huang, P., Peslak, S. A., Sharma, M., Abdulmalik, O., Giardine, B. M., Zhang, Z., Keller, C. A., Hardison, R. C., & Blobel, G. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Pennsylvania State University (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2020-05-28
- Volume
- 135
- Issue
- 22
- Pages
- 1957-1968
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC7256358
- OpenAlex
- W3014653639
- Semantic Scholar
- 3d815b244cfb8e99601545ada0fff3a9bbce7855
- Cited by
- 40
- References
- 64
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 11 · 2021: 4 · 2020: 5
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Society of Hematology
- Children's Hospital of Philadelphia
- St. Jude Children's Research Hospital
- National Institutes of Health (DK106766)
- National Heart, Lung, and Blood Institute (HL007150-42, HL119479, R01HL119479, T32HL007150, R35HL150698)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766, R01DK054937)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- fetal hemoglobin, erythroblasts, F cells, A cells, sickle cell disease, beta-thalassemia, hydroxyurea, pomalidomide, gamma-globin gene, beta-globin locus, BCL11A, LRF, erythroid differentiation, transcriptional regulation, epigenetic reprogramming
- MeSH terms
- Adult, Anemia, Sickle Cell, Cell Line, Cell Separation, Cells, Cultured, Erythroblasts, Fetal Hemoglobin, Hemoglobin A, Humans, Hydroxyurea, RNA, Messenger, Thalidomide, Gene Expression Profiling, Proteomics, Erythroid Cells
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