Five‐aminolevulinic acid: New approach for congenital sideroblastic anemia

Ishida, Hiroyuki; Imamura, Toshihiko; Morimoto, Akira; Fujiwara, Tohru; Harigae, Hideo

doi:10.1111/ped.13558

Cited by 4 publications

(5 citation statements)

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“…12A and B). Considering that ALA is an endogenous amino acid that has been shown to be safe in clinical settings (57), ALA may be a promising drug for XLSA, although a pharmacokinetics study showed that serum ALA concentration did not reach the sufficient levels seen in this study when administered at the currently used dose (58). Therefore, a dose escalation clinical trial is necessary to confirm the efficacy of ALA for XLSA.…”

Section: Discussionmentioning

confidence: 75%

Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation

Saito

Fujiwara

Hatta

et al. 2019

Molecular and Cellular Biology

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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 cell-derived 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.

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Section: Discussionmentioning

confidence: 75%

Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation

Saito

Fujiwara

Hatta

et al. 2019

Molecular and Cellular Biology

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“…However, the oral administration of ALA did not improve anemia in our patients, consistent with a reported case. 12 This may be due to the fact that the concentration of ALA in the bone marrow was not sufficient to improve the pathophysiology of MT cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, the oral administration of ALA did not improve anemia in our patients, consistent with a reported case. 12 This may be because the concentration of ALA in the bone marrow was not sufficient to improve the pathophysiology of MT cells. Drugs that increase the cellular uptake of ALA, especially in early erythroid cells, may improve the drug efficacy.…”

Section: Discussionmentioning

confidence: 99%

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Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia

et al. 2022

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X-linked sideroblastic anemia (XLSA) is associated with mutations in the erythroid-specific δ-aminolevulinic acid synthase (ALAS2) gene. Treatment for XLSA is mainly supportive, except in pyridoxine-responsive patients. Female XLSA often represents a late onset of severe anemia, mostly due to the acquired skewing of X-chromosome inactivation. Here, we successfully generated active wild-type and mutant ALAS2 induced pluripotent stem cell (iPSC) lines from the peripheral blood cells of an affected mother and two daughters in a family with pyridoxine-resistant XLSA due to a heterozygous ALAS2 missense mutation (R227C). The erythroid differentiation potential was severely impaired in active mutant iPSC lines compared to that in active wild-type iPSC lines. Most of the active mutant iPSC-derived erythroblasts revealed an immature morphological phenotype, and some showed dysplasia and perinuclear iron deposits. Additionally, globin and HO-1 expression and heme biosynthesis in active mutant erythroblasts were severely impaired compared to that in active wild-type erythroblasts. Furthermore, genes associated with erythroblast maturation and karyopyknosis showed significantly reduced expression in active mutant erythroblasts, recapitulating the maturation defects. Notably, the erythroid differentiation ability and hemoglobin expression of active mutant iPSC-derived hematopoietic progenitor cells (HPCs) were improved by the administration of δ-aminolevulinic acid, verifying the suitability of the cells for drug testing. Administration of a DNA demethylating agent, azacitidine, reactivated the silent wild-type ALAS2 allele in active mutant HPCs and ameliorated erythroid differentiation defects, suggesting that azacitidine is a potential novel therapeutic drug for female XLSA. Our patient-specific iPSC platform provides novel biological and therapeutic insights for XLSA.

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“…Although vitamin B6 is commonly used to treat XLSA, nearly half of the cases are unresponsive to treatment 4 , 5 , 18 . Additionally, oral ALA supplementation even failed to improve anemia in vitamin B6-refractory XLSA 19 . Thus, research of novel therapeutic strategies by clarifying the molecular basis of ring sideroblasts is required.…”

Section: Introductionmentioning

confidence: 99%

Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis

Ono

Fujiwara

Saito

et al. 2022

Sci Rep

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X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.

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Five‐aminolevulinic acid: New approach for congenital sideroblastic anemia

Cited by 4 publications

References 5 publications

Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation

Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation

Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia

Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis

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