Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

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Abstract
Erythroid 5‐aminolevulinate synthase (ALAS‐E) catalyzes the first step of heme biosynthesis in erythroid cells. Mutation of human ALAS‐E causes the disorder X‐linked sideroblastic anemia. To examine the roles of heme during hematopoiesis, we disrupted the mouse ALAS‐E gene. ALAS‐E‐null embryos showed no hemoglobinized cells and died by embryonic day 11.5, indicating that ALAS‐E is the principal isozyme contributing to erythroid heme biosynthesis. In the ALAS‐E‐null mutant embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. In contrast, we found typical ring sideroblasts that accumulated iron mostly in mitochondria in adult mice chimeric for ALAS‐E‐null mutant cells, indicating that the mode of iron accumulation caused by the lack of ALAS‐E is different in primitive and definitive erythroid cells. These results demonstrate that ALAS‐E, and hence heme supply, is necessary for differentiation and iron metabolism of erythroid cells.