Congenital Sideroblastic Anemia Model Due to ALAS2 Mutation is Susceptible to Ferroptosis

Overview

Journal Sci Rep

Specialty Science

Date 2022 May 31

PMID 35637209

Authors

Koya Ono

Tohru Fujiwara

Kei Saito

Hironari Nishizawa

Noriyuki Takahashi

Chie Suzuki

Tetsuro Ochi

Hiroki Kato

Yusho Ishii

Koichi Onodera

Satoshi Ichikawa

Noriko Fukuhara

Yasushi Onishi

Hisayuki Yokoyama

Rie Yamada

Yukio Nakamura

Kazuhiko Igarashi

Hideo Harigae

Affiliations

Soon will be listed here.

Abstract

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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References

Jensen P, Heickendorff L, Pedersen B, Jensen F, Christensen T, Boesen A . The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol. 1996; 94(2):288-99. DOI: 10.1046/j.1365-2141.1996.d01-1795.x. View

Morimoto Y, Chonabayashi K, Kawabata H, Okubo C, Yamasaki-Morita M, Nishikawa M . Azacitidine is a potential therapeutic drug for pyridoxine-refractory female X-linked sideroblastic anemia. Blood Adv. 2021; 6(4):1100-1114. PMC: 8864662. DOI: 10.1182/bloodadvances.2021005664. View

Canli O, Alankus Y, Grootjans S, Vegi N, Hultner L, Hoppe P . Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood. 2015; 127(1):139-48. PMC: 4705604. DOI: 10.1182/blood-2015-06-654194. View

Brinkman E, Kousholt A, Harmsen T, Leemans C, Chen T, Jonkers J . Easy quantification of template-directed CRISPR/Cas9 editing. Nucleic Acids Res. 2018; 46(10):e58. PMC: 6007333. DOI: 10.1093/nar/gky164. View

Gattermann N, Finelli C, Porta M, Fenaux P, Stadler M, Guerci-Bresler A . Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica. 2012; 97(9):1364-71. PMC: 3436237. DOI: 10.3324/haematol.2011.048546. View

Edgar A, Vidyatilake H, Wickramasinghe S . X-linked sideroblastic anaemia due to a mutation in the erythroid 5-aminolaevulinate synthase gene leading to an arginine170 to leucine substitution. Eur J Haematol. 1998; 61(1):55-8. DOI: 10.1111/j.1600-0609.1998.tb01061.x. View

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

Ohba R, Furuyama K, Yoshida K, Fujiwara T, Fukuhara N, Onishi Y . Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS). Ann Hematol. 2012; 92(1):1-9. PMC: 3536986. DOI: 10.1007/s00277-012-1564-5. View

Faller M, Matsunaga M, Yin S, Loo J, Guo F . Heme is involved in microRNA processing. Nat Struct Mol Biol. 2006; 14(1):23-9. DOI: 10.1038/nsmb1182. View

10.

Cazzola M, Malcovati L . Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing. Hematology Am Soc Hematol Educ Program. 2015; 2015:19-25. DOI: 10.1182/asheducation-2015.1.19. View

11.

Linkermann A, Skouta R, Himmerkus N, Mulay S, Dewitz C, De Zen F . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014; 111(47):16836-41. PMC: 4250130. DOI: 10.1073/pnas.1415518111. View

12.

Kaneko K, Furuyama K, Fujiwara T, Kobayashi R, Ishida H, Harigae H . Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia. Haematologica. 2013; 99(2):252-61. PMC: 3912954. DOI: 10.3324/haematol.2013.085449. View

13.

Bottomley S, Fleming M . Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am. 2014; 28(4):653-70, v. DOI: 10.1016/j.hoc.2014.04.008. View

14.

Zhang Y, Zhang J, An W, Wan Y, Ma S, Yin J . Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation. Nucleic Acids Res. 2017; 45(2):657-671. PMC: 5314798. DOI: 10.1093/nar/gkw901. View

15.

Saito K, Fujiwara T, Hatta S, Morita M, Ono K, Suzuki C . Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation. Mol Cell Biol. 2019; 39(7). PMC: 6425143. DOI: 10.1128/MCB.00387-18. View

16.

Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz E . Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica. 2010; 95(8):1433-4. PMC: 2913096. DOI: 10.3324/haematol.2010.024992. View

17.

Altamura S, Vegi N, Hoppe P, Schroeder T, Aichler M, Walch A . Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis. Haematologica. 2019; 105(4):937-950. PMC: 7109755. DOI: 10.3324/haematol.2018.212977. View

18.

Katsurada T, Kawabata H, Kawabata D, Kawahara M, Nakabo Y, Takaori-Kondo A . A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia. Int J Hematol. 2016; 103(6):713-7. DOI: 10.1007/s12185-016-1949-7. View

19.

Fibach E, Rachmilewitz E . The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia. Ann N Y Acad Sci. 2010; 1202:10-6. DOI: 10.1111/j.1749-6632.2010.05577.x. View

20.

Rose C, Callebaut I, Pascal L, Oudin C, Fournier M, Gouya L . Lethal ALAS2 mutation in males X-linked sideroblastic anaemia. Br J Haematol. 2016; 178(4):648-651. DOI: 10.1111/bjh.14164. View