Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in β-thalassemia mouse model Short Title : Thalassemia treatment by heme oxygenase inhibition

220; Text: 4394; Figures: 6; References: 64. Blood First Edition Paper, prepublished online November 27, 2017; DOI 10.1182/blood-2017-07-798728 Copyright © 2017 American Society of Hematology For personal use only. on November 29, 2017. by guest www.bloodjournal.org From

[1]  A. English,et al.  Do Mammalian Cells Really Need to Export and Import Heme? , 2017, Trends in biochemical sciences.

[2]  S. Rivella,et al.  Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera. , 2016, Blood.

[3]  R. Weissleder,et al.  On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver , 2016, Nature Medicine.

[4]  B. Liu,et al.  Cytoprotective role of heme oxygenase-1 in liver ischemia reperfusion injury. , 2015, International journal of clinical and experimental medicine.

[5]  T. Ganz,et al.  Ironing out Ferroportin. , 2015, Cell metabolism.

[6]  T. Ganz,et al.  Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. , 2015, Blood.

[7]  S. Rivella β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies , 2015, Haematologica.

[8]  M. Fleming,et al.  Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β-thalassemia intermedia , 2015, American journal of hematology.

[9]  A. Habtezion,et al.  Protective role of hemeoxygenase-1 in gastrointestinal diseases , 2015, Cellular and Molecular Life Sciences.

[10]  S. Rivella,et al.  Iron age: novel targets for iron overload. , 2014, Hematology. American Society of Hematology. Education Program.

[11]  S. Rivella,et al.  IDENTIFICATION OF ERYTHROFERRONE AS AN ERYTHROID REGULATOR OF IRON METABOLISM , 2014, Nature Genetics.

[12]  D. Garcia-Santos,et al.  Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme. , 2014, Blood.

[13]  T. Ganz Systemic iron homeostasis. , 2013, Physiological reviews.

[14]  Ju Hwan Lee,et al.  Antidiabetic Potential of the Heme Oxygenase-1 Inducer Curcumin Analogues , 2013, BioMed research international.

[15]  S. Rivella,et al.  Non-transfusion-dependent thalassemias , 2013, Haematologica.

[16]  S. Rivella,et al.  Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. , 2013, The Journal of clinical investigation.

[17]  S. Milstein,et al.  An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. , 2013, Blood.

[18]  M. Lidonnici,et al.  Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia. , 2012, Blood.

[19]  D. Stevenson,et al.  Metalloporphyrins – An Update , 2012, Front. Pharmacol..

[20]  Elizabeta Nemeth,et al.  Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. , 2011, The Journal of clinical investigation.

[21]  Jiyu Li,et al.  Dual protective role of HO-1 in transplanted liver grafts: a review of experimental and clinical studies. , 2011, World journal of gastroenterology.

[22]  R. Paulson,et al.  Stress erythropoiesis: new signals and new stress progenitor cells , 2011, Current opinion in hematology.

[23]  D. Stevenson,et al.  In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins , 2011, Journal of Perinatology.

[24]  S. Rivella Ineffective erythropoiesis and thalassemias , 2009, Current opinion in hematology.

[25]  B. Andriopoulos,et al.  Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo , 2009, Proceedings of the National Academy of Sciences.

[26]  H. Puy,et al.  Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. , 2008, The Biochemical journal.

[27]  N. Abraham,et al.  Pharmacological and Clinical Aspects of Heme Oxygenase , 2008, Pharmacological Reviews.

[28]  P. Sathyanarayana,et al.  EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts. , 2007, Blood.

[29]  A. Levchenko,et al.  Negative Autoregulation by FAS Mediates Robust Fetal Erythropoiesis , 2007, PLoS biology.

[30]  F. Lang,et al.  Enhanced suicidal death of erythrocytes from gene-targeted mice lacking the Cl-/ HCO ( 3 ) (-) exchanger AE 1 , 2009 .

[31]  Jane-Jane Chen Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. , 2007, Blood.

[32]  D. Wojchowski,et al.  Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis. , 2006, The Journal of clinical investigation.

[33]  L. Otterbein,et al.  Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. , 2006, The Journal of clinical investigation.

[34]  M. Maines The heme oxygenase system: update 2005. , 2005, Antioxidants & redox signaling.

[35]  Masafumi Yamamoto,et al.  Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells. , 2004, The Journal of biological chemistry.

[36]  S. Schrier Pathophysiology of thalassemia , 2002, Current opinion in hematology.

[37]  H. Lodish,et al.  Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. , 2001, Blood.

[38]  C. Lok,et al.  Identification of an Erythroid Active Element in the Transferrin Receptor Gene* , 2000, The Journal of Biological Chemistry.

[39]  I. Weissman,et al.  The monoclonal antibody TER‐119 recognizes a molecule associated with glycophorin A and specifically marks the late stages of murine erythroid lineage , 2000, British journal of haematology.

[40]  M. Garrick,et al.  Evidence for and consequences of chronic heme deficiency in Belgrade rat reticulocytes. , 1999, Biochimica et biophysica acta.

[41]  S. Tonegawa,et al.  Heme oxygenase 1 is required for mammalian iron reutilization. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Detloff,et al.  A mouse model for beta 0-thalassemia. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Tyrrell,et al.  Ultraviolet A (320-380 nm) radiation causes an alteration in the binding of a specific protein/protein complex to a short region of the promoter of the human heme oxygenase 1 gene. , 1993, Nucleic acids research.

[44]  G. Drummond,et al.  Prolonged clinical use of a heme oxygenase inhibitor: hematological evidence for an inducible but reversible iron-deficiency state. , 1993, Pediatrics.

[45]  H. Munro,et al.  Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  B. Angelin,et al.  Sn‐protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase activity in normal human subjects , 1988, Hepatology.

[47]  L. Cucchiarini,et al.  Effect of age on some properties of mice erythrocytes , 1988, Mechanisms of Ageing and Development.

[48]  S. Shibahara,et al.  Transcriptional control of rat heme oxygenase by heat shock. , 1987, The Journal of biological chemistry.

[49]  B. Ames,et al.  Bilirubin is an antioxidant of possible physiological importance. , 1987, Science.

[50]  K. Anderson,et al.  The liver excretes large amounts of heme into bile when heme oxygenase is inhibited competitively by Sn-protoporphyrin. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Sassa,et al.  Sequential induction of heme pathway enzymes during erythroid differentiation of mouse Friend leukemia virus-infected cells , 1976, The Journal of experimental medicine.

[52]  P. Ponka,et al.  Evidence for the presence of free and protein-bound nonhemoglobin heme in rabbit reticulocytes. , 1972, Biochimica et biophysica acta.

[53]  J. Greer,et al.  Wintrobe's clinical hematology 13Ed , 2013 .

[54]  A. Gow,et al.  Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. , 2004, The Journal of clinical investigation.

[55]  S. Sassa Why heme needs to be degraded to iron, biliverdin IXalpha, and carbon monoxide? , 2004, Antioxidants & redox signaling.

[56]  K. Igarashi,et al.  Heme-dependent up-regulation of the alpha-globin gene expression by transcriptional repressor Bach1 in erythroid cells. , 2004, Biochemical and biophysical research communications.

[57]  P. Ponka Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. , 1997, Blood.

[58]  M. Maines,et al.  The heme oxygenase system: a regulator of second messenger gases. , 1997, Annual review of pharmacology and toxicology.

[59]  S. Schrier,et al.  The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia. , 1990, Blood.

[60]  R. Tyrrell,et al.  Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[61]  M. Cazzola,et al.  Iron metabolism in thalassemia. , 1988, Birth defects original article series.

[62]  J. B. Clegg,et al.  The thalassaemia syndromes , 1965 .

[63]  C. Finch,et al.  Erythrokinetics in Cooley's anemia. , 1957, Blood.