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Pharmacologic induction of human fetal hemoglobin through activation of the NRF2 antioxidant response signaling pathway

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Author	Macari, Elizabeth R.
Title	Pharmacologic induction of human fetal hemoglobin through activation of the NRF2 antioxidant response signaling pathway
Date	2012
Abstract	Pharmacologic induction of fetal hemoglobin (HbF) has proven therapeutic potential for ß-hemoglobinopathy patients. Increased HbF reduces disease severity by decreasing sickling in sickle cell disease and reducing α-chain imbalance in ß-thalassemia. Over 70 compounds have been described that increase HbF, however, none of these agents have the ideal combination of safety, efficacy and ease of use. The work presented here focused on identifying new targets and agents that can stimulate HbF without causing DNA damage or altering epigenetic structure. One of these targets, nuclear erythroid factor 2-related factor 2 (NRF2), is the master regulator of antioxidant and detoxification signaling. We found three NRF2 activators that significantly induced γ-globin mRNA. Using the most active compound, tert-butylhydroquinone (tBHQ), we showed that NRF2 is required but not sufficient for full induction of γ-globin gene expression in K562 cells. tBHQ treatment of primary human erythroid cells resulted in NRF2 binding to the γ-globin promoters and to HS2 of the ß-globin locus control region (LCR), and increased γ-globin mRNA and HbF, and suppressed ß-globin mRNA. We also investigated a potential synergy between activators of NRF2 and another transcription factor, KLF2. Simvastatin dose-dependently induced KLF2 mRNA and protein in K562 cells. Co-treatment with simvastatin and tBHQ significantly enhanced γ-globin gene expression, which requires KLF2. Additionally, KLF2 binds to HS2 of the ß-globin LCR in K562 cells and significantly increases after treatment with simvastatin alone or simvastatin plus tBHQ. Treatment of primary human erythroid cells with simvastatin or tBHQ increased γ-globin mRNA and decreased ß-globin, KLF1 and BCL11A mRNA. The combination of simvastatin and tBHQ increased HbF and decreased HbA production more than either drug alone. Since the major γ-globin repressor, BCL11A, is a direct target of KLF1, we investigated mechanisms for tBHQ-mediated reduction of KLF1. Our preliminary data suggests that tBHQ inhibits Smad signaling which may contribute to KLF1 suppression. Overall, we show that two FDA-approved agents induce NRF2 and KLF2 in erythroid cells and when used in combination can achieve therapeutic levels of HbF. We hope this work leads to safe, effective, and widely available agents for HbF induction.
Description	x, 135 leaves : ill. ; 28 cm.
Format	application/pdf
Advisor	Lowrey, Christopher; Eastman, Alan R; Fiering, Steve; Gallagher, Patrick; Tomlinson, Craig
College	Dartmouth Medical School -- Experimental and Molecular Medicine Program.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.417

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	PHARMACOLOGIC INDUCTION OF HUMAN FETAL HEMOGLOBIN THROUGH ACTIVATION OF THE NRF2 ANTIOXIDANT RESPONSE SIGNALING PATHWAY A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental and Molecular Medicine By Elizabeth R. Macari Dartmouth College Hanover, New Hampshire May 31, 2012 Examining Committee ___________________________ (Chair) Christopher H. Lowrey, M.D. ___________________________ Alan R. Eastman, Ph.D. ___________________________ Steve Fiering, Ph.D. ___________________________ Patrick G. Gallagher, M.D. ___________________________ ________________________ Craig Tomlinson, Ph.D. Brian W. Pogue, Ph.D. Dean of Graduate Studies

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