5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin

R. K. Humphries, George J Dover, N. S. Young, J. G. Moore, S. Charache, T. Ley, A. W. Nienhuis

Research output: Contribution to journalArticle

Abstract

The effect of 5-azacytidine on erythroid precursors and progenitors was studied in nine patients with sickle cell anemia or severe thalassemia. Each patient received the drug intravenously for 5 or 7 d. 5-Azacytidine caused a four- to sixfold increase in γ-messenger RNA concentration in bone marrow cells of eight of the nine patients and decreased the methylation frequency of a specific cytosine residue in the γ-globin gene promoter in all nine patients. Within 2 d of the start of drug treatment there was a rise in the percentage of reticulocytes containing fetal hemoglobin (HbF; F-reticulocytes) without a significant change in the total number of reticulocytes, which suggested that there was a direct action of 5-azacytidine on erythroid precursors. Late erythroid progenitors (CFU-E), present in bone marrow after 2 d of drug administration, formed colonies containing an increased amount of HbF as compared with control colonies. Moreover, the number of CFU-E derived colonies was not decreased at these early times, which suggested that there was a direct action of 5-azacytidine on erythroid progenitors in the absence of cytotoxicity. Exposure of normal bone marrow cells in tissue culture to 5-azacytidine for 24 h reproduced both of these effects as judged during subsequent colony formation. The combined direct effects of 5-azacytidine on both the erythroid precursor and progenitor compartments resulted in an increase in HbF synthesis that was sustained for 2-3 wk. Toxicity to bone marrow as reflected by cytoreduction was evident after treatment in some patients but was not accompanied by an increase in HbF production. A correlation was found between the effects of 5-azacytidine on bone marrow, as assessed by in vitro measurements, and the hematological response of the individual patients to drug treatment.

Original languageEnglish (US)
Pages (from-to)547-557
Number of pages11
JournalJournal of Clinical Investigation
Volume75
Issue number2
StatePublished - 1985
Externally publishedYes

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Azacitidine
Fetal Hemoglobin
Erythroid Precursor Cells
Bone Marrow
Reticulocytes
Bone Marrow Cells
Pharmaceutical Preparations
Reticulocyte Count
Thalassemia
Globins
Cytosine
Sickle Cell Anemia
Methylation
Therapeutics
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Humphries, R. K., Dover, G. J., Young, N. S., Moore, J. G., Charache, S., Ley, T., & Nienhuis, A. W. (1985). 5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. Journal of Clinical Investigation, 75(2), 547-557.

5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. / Humphries, R. K.; Dover, George J; Young, N. S.; Moore, J. G.; Charache, S.; Ley, T.; Nienhuis, A. W.

In: Journal of Clinical Investigation, Vol. 75, No. 2, 1985, p. 547-557.

Research output: Contribution to journalArticle

Humphries, RK, Dover, GJ, Young, NS, Moore, JG, Charache, S, Ley, T & Nienhuis, AW 1985, '5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin', Journal of Clinical Investigation, vol. 75, no. 2, pp. 547-557.
Humphries, R. K. ; Dover, George J ; Young, N. S. ; Moore, J. G. ; Charache, S. ; Ley, T. ; Nienhuis, A. W. / 5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. In: Journal of Clinical Investigation. 1985 ; Vol. 75, No. 2. pp. 547-557.
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AU - Charache, S.

AU - Ley, T.

AU - Nienhuis, A. W.

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