Generation and molecular characterization of human ring sideroblasts: A key role of ferrous iron in terminal erythroid differentiation and ring sideroblast formation

Kei Saito, Tohru Fujiwara, Shunsuke Hatta, Masanobu Morita, Koya Ono, Chie Suzuki, Noriko Fukuhara, Yasushi Onishi, Yukio Nakamura, Shin Kawamata, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae

Research output: Contribution to journalArticlepeer-review

Abstract

Ring sideroblasts are a hallmark of sideroblastic anemia, although little is known about their characteristics. Here, we first generated mutant mice by disrupting the GATA-1 binding motif at the intron 1 enhancer of the ALAS2 gene, a gene responsible for X-linked sideroblastic anemia (XLSA). Although heterozygous female mice showed an anemic phenotype, ring sideroblasts were not observed in their bone marrow. We next established human induced pluripotent stem cellderived proerythroblast clones harboring the same ALAS2 gene mutation. Through coculture with sodium ferrous citrate, mutant clones differentiated into mature erythroblasts and became ring sideroblasts with upregulation of metal transporters (MFRN1, ZIP8, and DMT1), suggesting a key role for ferrous iron in erythroid differentiation. Interestingly, holo-transferrin (holo-Tf) did not induce erythroid differentiation as well as ring sideroblast formation, and mutant cells underwent apoptosis. Despite massive iron granule content, ring sideroblasts were less apoptotic than holo-Tf-treated undifferentiated cells. Microarray analysis revealed upregulation of antiapoptotic genes in ring sideroblasts, a profile partly shared with erythroblasts from a patient with XLSA. These results suggest that ring sideroblasts exert a reaction to avoid cell death by activating antiapoptotic programs. Our model may become an important tool to clarify the pathophysiology of sideroblastic anemia.

Original languageEnglish
Article numbere00387-18
JournalMolecular and cellular biology
Volume39
Issue number7
DOIs
Publication statusPublished - 2019 Apr 1

Keywords

  • 5-aminolevulinic acid synthase 2
  • Erythroid cells
  • Heme
  • Iron
  • X-linked sideroblastic anemia

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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