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| Status |
Public on Nov 01, 2017 |
| Title |
Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Sickle cell disease (SCD) results from a point mutation in the β-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)–like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell–derived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate γ-globin transcription and enhance HbF in tissue culture, murine and primate models. DMF recruited Nrf2 to the γ-globin promoters and the locus control region of the β-globin locus in erythroleukemia cells, elevated HbF in SCD donor–derived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased γ-globin mRNA in BM and HbF protein in red cells. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification
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| Overall design |
RNA-Seq of 30 samples
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| Contributor(s) |
Krishnamoorthy S, Pace B, Gupta D, Sturtevant S, Li B, Makala L, Brittain J, Moore N, Vieira BF, Thullen T, Stone I, Li H, Hobbs WE, Light DR |
| Citation(s) |
29046485 |
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| Submission date |
Oct 16, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Suzanne Szak |
| Organization name |
BiogenIdec, Inc.
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| Department |
Drug Discovery
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| Street address |
14 Cambridge Ctr
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA414450 |
| SRA |
SRP120038 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE105035_gene.estcount_table.txt.gz |
698.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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