γ-Globin promoter activation in erythroid progenitors through multiple targets by short-chain fatty acid derivatives

2007 ◽  
Vol 38 (2) ◽  
pp. 158
Author(s):  
Rishikesh Mankidy ◽  
Douglas V. Faller ◽  
Susan P. Perrine
Keyword(s):  
Fatty Acid ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Promoter Activation ◽  
Erythroid Progenitors ◽  
Multiple Targets ◽  
Fatty Acid Derivatives ◽  
Globin Promoter

scholarly journals Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4640-4648 ◽  
Author(s):  
Betty S. Pace ◽  
Gary L. White ◽  
George J. Dover ◽  
Michael S. Boosalis ◽  
Douglas V. Faller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Short Chain Fatty Acid ◽  
Globin Gene ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Pharmacokinetic Studies ◽  
Fatty Acid Derivatives ◽  
Globin Gene Expression

Orally bioactive compounds that induce γ globin gene expression at tolerable doses are needed for optimal treatment of the β-hemoglobinopathies. Short-chain fatty acids (SCFAs) of 2 to 6 carbons in length induce γ globin expression in animal models, and butyrate, phenylbutyrate, and valproate induce γ globin in human patients. The usefulness of these compounds, however, is limited by requirements for large doses because of their rapid metabolism and their tendency to inhibit cell proliferation, which limits the pool of erythroid progenitors in which γ globin can be induced. Selected short-chain fatty acid derivatives (SCFADs) were recently found to induce γ globin and to stimulate the proliferation of hematopoietic cells in vitro. These SCFADs are now evaluated in vivo in nonanemic transgenic mice containing the human β globin gene locus and in anemic phlebotomized baboons. In mice treated with a SCFAD once daily for 5 days, γ globin mRNA increased 2-fold, reticulocytes increased 3- to 7-fold, and hematocrit levels increased by 27%. Administration of 3 SCFADs in anemic baboons increased F-reticulocytes 2- to 15-fold over baseline and increased total hemoglobin levels by 1 to 2 g/dL per week despite ongoing significant daily phlebotomy. Pharmacokinetic studies demonstrated 90% oral bioavailability of 2 SCFADs, and targeted plasma levels were maintained for several hours after single oral doses equivalent to 10% to 20% of doses required for butyrate. These findings identify SCFADs that stimulate γ globin gene expression and erythropoiesis in vivo, activities that are synergistically beneficial for treatment of the β hemoglobinopathies and useful for the oral treatment of other anemias.

scholarly journals Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3259-3267 ◽  
Author(s):  
Michael S. Boosalis ◽  
Ram Bandyopadhyay ◽  
Emery H. Bresnick ◽  
Betty S. Pace ◽  
Karyn Van DeMark ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cellular Proliferation ◽  
Short Chain Fatty Acid ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Chain Fatty Acid ◽  
Cellular Growth ◽  
Short Chain ◽  
Hemoglobin F ◽  
Fatty Acid Derivatives

Abstract Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous γ-globin expression in K562 cells and human burst-forming units–erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3–dependent hematopoietic cell line. In this report, γ-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire β-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb andc-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cisexpression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21Waf/Cip, which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and STAT-5 activation, contribute to the cellular proliferation induced by selected SCFADs.

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