A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells.

Blood
Natarajan V BhanuJeffery L Miller

Abstract

We systematically compared cytokine-mediated increases or decreases in proliferation with globin gene and protein expression in adult human erythroblasts. Despite their opposite effects on growth, stem cell factor (SCF) and transforming growth factor beta (TGF-B) had synergistic effects with respect to fetal hemoglobin (HbF): average HbF/HbF + adult hemoglobin (HbA) ratio in erythropoietin (EPO) = 1.4 +/- 1.0%; EPO + TGF-B = 10.8 +/- 1.9%; EPO + SCF = 19.1 +/- 6.2%; and EPO + SCF + TGF-B (EST) = 39.3 +/- 6.3%. Polymerase chain reaction (PCR) revealed significant increases in gamma-globin transcripts that were balanced by reduced beta-globin transcripts. Single-cell quantitative PCR demonstrated a complete reversal of gamma-globin gene silencing with detectable gamma-globin mRNA in more than 95% of the cells. Immunostaining with HbF antibodies also showed a pancellular distribution in EST (96.2 +/- 0.01% HbF positive) compared with a heterocellular distribution in EPO (42.9 +/- 0.01% HbF positive). As shown here for the first time, a robust and pancellular reversal of gamma-globin gene silencing among hemoglobinized erythroblasts from adult humans may be achieved in the absence of hereditary mutation or direct genomic manipulation.

References

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Nov 1, 2003·Blood·Natarajan V BhanuJeffery L Miller

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Citations

Dec 16, 2010·Current Opinion in Pediatrics·Daniel E Bauer, Stuart H Orkin
Jun 1, 2006·Blood·Patricia A OnealJeffery L Miller
Jan 1, 2009·Mediterranean Journal of Hematology and Infectious Diseases·Marco Gabbianelli, Ugo Testa
Apr 6, 2007·British Journal of Haematology·Natarajan V BhanuJeffery L Miller
Apr 12, 2006·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Betty S Pace, Sima Zein
Jul 7, 2007·British Journal of Haematology·Lakiea BaileyTohru Ikuta
Jun 29, 2012·Transfusion·Eugenia Prus, Eitan Fibach
Apr 15, 2011·Blood·Idowu AkinsheyeMartin H Steinberg
Jul 1, 2005·Transfusion·Jeffery L Miller
Oct 27, 2017·International Journal of Hematology·Pinyaphat KhamphikhamDuncan R Smith
Feb 26, 2021·Current Opinion in Hematology·Eugene Khandros, Gerd A Blobel
Nov 17, 2020·Biochemistry and Biophysics Reports·Yasser AbdElsattar ElghobashySaher Elmasry

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