Impact of TET2 deficiency on iron metabolism in erythroblasts.
Sideroblastic anemia is characterized by the presence of ring sideroblasts (RSs), which are caused by iron accumulation in the mitochondria of erythroblasts and are present in both the acquired and congenital forms of the disease. However, the mechanism leading to RS formation remains elusive. Acquired sideroblastic anemia is usually observed in myelodysplastic syndrome (MDS). Because a subset of MDS harbors a somatic mutation of TET2, it may be involved in iron metabolism and/or heme biosynthesis in erythroblasts. Tet2 knockdown (Tet2trap) induced exhibited mild normocytic anemia and elevated serum ferritin levels in 4-month-old mice. Although typical RSs were not observed, increased mitochondrial ferritin (FTMT) amounts were observed in the erythroblasts of Tet2-knockdown mice. Quantitative real-time polymerase chain reaction demonstrated significant dysregulation of genes involved in iron and heme metabolism, including Hmox1, Fech, Abcb7, and Sf3b1 downregulation. After the identification of a cytosine-guanine island in the promoters of Fech, Abcb7, and Sf3b1, we evaluated DNA methylation status and found significantly higher methylation levels at the CpG sites in the erythroblasts of Tet2-knockdown mice. Furthermore, Tet2 knockdown in erythroblasts resulted in decreased heme concentration and accumulation of FTMT. Therefore, TET2 plays a role in the iron and heme metabolism in erythroblasts.
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Kyoko
K
Inokura
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan; Department of Molecular Hematology/Oncology, Tohoku University Graduate School, Sendai, Japan.
Tohru
T
Fujiwara
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Kei
K
Saito
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Tatsuya
T
Iino
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Shunsuke
S
Hatta
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Yoko
Y
Okitsu
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Noriko
N
Fukuhara
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan.
Yasushi
Y
Onishi
Department of Hematology and Cell Therapy, Yamagata University Faculty of Medicine, Yamagata, Japan.
Kenichi
K
Ishizawa
Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, Miyazaki University, Miyazaki, Japan.
Kazuya
K
Shimoda
Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai, Japan; Department of Molecular Hematology/Oncology, Tohoku University Graduate School, Sendai, Japan. Electronic address: harigae@med.tohoku.ac.jp.
Hideo
H
Harigae
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism*; D049308:Dioxygenases; D004900:Erythroblasts / Q000378:metabolism*; D006418:Heme / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism*; D000072260:RNA Splicing Factors / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction
C571883:ABCB8 protein, mouse; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000072260:RNA Splicing Factors; C491799:Sf3b1 protein, mouse; D006418:Heme; D007501:Iron; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse