Fetal hemoglobin (HbF)-expressing cells may not be significantly different from F-erythroblasts, with primary differences occurring at the beta-globin locus, according to research published in Blood.

HbF expression reactivation in adult erythroblasts is important for disease management in both sickle cell disease (SCD) and β-thalassemia. While elevated HbF levels have been noted in patients with SCD, these can also be found in healthy individuals, and are usually distributed, in a heterocellular manner, in F cells. Previous therapeutic approaches have aimed to increase the number of F cells containing a threshold HbF level to counteract sickling in SCD; however, the reason why some genetically identical cells, and not others, have increased HbF production in response to treatment remains unclear.

As the lack of clarity on HbF production may be due to technical difficulties in analyzing F cells, a team of investigators developed novel techniques, which allow them to purify and differentiate stage-matched erythroblast F-cells and non-F cells (A cells).

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Neither transcriptional nor proteomic profiling revealed significant differences between F and A cells at baseline, or after HbF-inducing treatment. No differences in expression of known regulators of HbF were noted, suggesting that the main differences between F and A cells occur at the transcriptional level at the beta-globin locus.

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“Future imaging and chromatin configuration studies will characterize F-cells at the epigenetic and transcriptional bursting level under different conditions,” the authors concluded. “Our methods will allow for further interrogation of F-cells generated in response to different stimuli and will further help understand regulation of globin switching.”


Khandros E, Huang P, Peslak SA, et al. Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F- and A-erythroblasts [published online April 8, 2020]. Blood. doi: 10.1182/blood.2020005058