1.
Bottomley SS, Fleming MD. Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am. 2014;28(4):653-670, v.
2.
Yamamoto M, Yew NS, Federspiel M, Dodgson JB, Hayashi N, Engel JD. Isolation of recombinant cDNAs encoding chicken erythroid deltaaminolevulinate synthase. Proc Natl Acad Sci USA. 1985;82(11):3702-3706.
3.
Ducamp S, Fleming MD. The molecular genetics of sideroblastic anemia. Blood. 2019;133(1):59-69.
4.
Aivado M, Gattermann N, Rong A, et al. X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed
X-chromosome inactivation patterns. Blood Cells Mol Dis. 2006;37(1):40-45.
5.
Sankaran VG, Ulirsch JC, Tchaikovskii V, et al. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. J Clin Invest.
2015;125(4):1665-1669.
6.
Katsurada T, Kawabata H, Kawabata D, et al. A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic
anemia. Int J Hematol. 2016;103(6):713-717.
7.
Rose C, Callebaut I, Pascal L, et al. Lethal ALAS2 mutation in males X-linked sideroblastic anaemia. Br J Haematol. 2017;178(4):648-651.
8.
Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF. Familial-skewed X-chromosome inactivation as a predisposing factor for lateonset X-linked sideroblastic anemia in carrier females. Blood. 2000;96(13):4363-4365.
9.
Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for
genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010;54(2):273-278.
22 FEBRUARY 2022 • VOLUME 6, NUMBER 4
XLSA AMELIORATION BY THE DEMETHYLATING AGENT AZA
1113
Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1100/1870480/advancesadv2021005664.pdf by guest on 22 June 2022
Last, we focused on the unusual disease mechanism of XLSA in
females, which is caused by the acquired skewing of X-chromosome
inactivation in hematopoietic stem cells. We speculated that the restoration of the expression of WT ALAS2 in a considerable number
of affected erythroblasts could ameliorate disease phenotypes in
female patients with XLSA. This study provides the first proof of concept that the silent WT ALAS2 allele in female subjects could be
partially reactivated by the DNA demethylating agent AZA, which
serves as a potential novel therapeutic approach for the treatment of
refractory anemia in female patients with XLSA (Figure 7). Although
the demethylating effect of AZA is global and off-target side effects
may occur in both hematopoietic and nonhematopoietic tissues,
AZA is currently being used in clinical practice to treat hematological malignancies and has shown acceptable adverse effects. However, the efficacy of AZA in our XLSA model is limited, and further
studies using DNA demethylating agents are needed for future
therapeutic use.
A Self-archived copy in
Kyoto University Research Information Repository
https://repository.kulib.kyoto-u.ac.jp
10. Ohba R, Furuyama K, Yoshida K, et al. Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic
syndrome with ring sideroblast (MDS-RS). Ann Hematol. 2013;92(1):1-9.
11. Astner I, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW. Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme
biosynthesis, and its link to XLSA in humans. EMBO J. 2005;24(18):3166-3177.
12. Ishida H, Imamura T, Morimoto A, Fujiwara T, Harigae H. Five-aminolevulinic acid: New approach for congenital sideroblastic anemia. Pediatr Int
(Roma). 2018;60(5):496-497.
13. Nakajima O, Takahashi S, Harigae H, et al. Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload. EMBO
J. 1999;18(22):6282-6289.
14. Nakajima O, Okano S, Harada H, et al. Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes. Genes Cells. 2006;11(6):685-700.
16. Hatta S, Fujiwara T, Yamamoto T, et al. A defined culture method enabling the establishment of ring sideroblasts from induced pluripotent cells of
X-linked sideroblastic anemia. Haematologica. 2018;103(5):e188-e191.
17. Kaneko K, Kubota Y, Nomura K, et al. Establishment of a cell model of X-linked sideroblastic anemia using genome editing. Exp Hematol. 2018;65:
57-68.e2.
18. Saito K, Fujiwara T, Hatta S, et al. 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):e00387-18.
19. Okita K, Yamakawa T, Matsumura Y, et al. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord
blood and peripheral blood cells. Stem Cells. 2013;31(3):458-466.
20. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;
126(4):663-676.
21. Boudewijns M, van Dongen JJ, Langerak AW. The human androgen receptor X-chromosome inactivation assay for clonality diagnostics of natural
killer cell proliferations. J Mol Diagn. 2007;9(3):337-344.
22. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the
human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992;51(6):1229-1239.
23. Grigoriadis AE, Kennedy M, Bozec A, et al. Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS
cells. Blood. 2010;115(14):2769-2776.
24. Nishizawa M, Chonabayashi K, Nomura M, et al. Epigenetic Variation between Human Induced Pluripotent Stem Cell Lines Is an Indicator of
Differentiation Capacity. Cell Stem Cell. 2016;19(3):341-354.
25. Kurita R, Suda N, Sudo K, et al. Establishment of immortalized human erythroid progenitor cell lines able to produce enucleated red blood cells.
PLoS One. 2013;8(3):e59890.
26. Kotini AG, Chang CJ, Chow A, et al. Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to
Transplantable Leukemia. Cell Stem Cell. 2017;20(3):315-328.e7.
27. Tokutomi T, Fukushima A, Yamamoto K, Bansho Y, Hachiya T, Shimizu A. f-treeGC: a questionnaire-based family tree-creation software for genetic
counseling and genome cohort studies. BMC Med Genet. 2017;18(1):71.
28. Huang P, Zhao Y, Zhong J, et al. Putative regulators for the continuum of erythroid differentiation revealed by single-cell transcriptome of human
BM and UCB cells. Proc Natl Acad Sci USA. 2020;117(23):12868-12876.
29. Ng KM, Mok PY, Butler AW, et al. Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor. Circulation. 2016;134(18):1373-1389.
30. Donker AE, Raymakers RA, Nieuwenhuis HK, et al. X-linked sideroblastic anaemia due to ALAS2 mutations in the Netherlands: a disease in
disguise. Neth J Med. 2014;72(4):210-217.
31. Cotter PD, May A, Fitzsimons EJ, et al. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase
(ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest. 1995;
96(4):2090-2096.
32. Fujiwara T, Fukuhara N, Ichikawa S, et al. A novel heterozygous ALAS2 mutation in a female with macrocytic sideroblastic anemia resembling
myelodysplastic syndrome with ring sideroblasts: a case report and literature review. Ann Hematol. 2017;96(11):1955-1957.
33. Ananiev G, Williams EC, Li H, Chang Q. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome
patients as in vitro disease model. PLoS One. 2011;6(9):e25255.
34. Reboun
M, Rybov
a J, Dobrovolny R, et al. X-Chromosome Inactivation Analysis in Different Cell Types and Induced Pluripotent Stem Cells
Elucidates the Disease Mechanism in a Rare Case of Mucopolysaccharidosis Type II in a Female. Folia Biol (Praha). 2016;62(2):82-89.
35. Trakarnsanga K, Wilson MC, Heesom KJ, Andrienko TN, Srisawat C, Frayne J. Secretory factors from OP9 stromal cells delay differentiation and
increase the expansion potential of adult erythroid cells in vitro. Sci Rep. 2018;8(1):1983.
36. Fujiwara T, Okamoto K, Niikuni R, et al. Effect of 5-aminolevulinic acid on erythropoiesis: a preclinical in vitro characterization for the treatment of
congenital sideroblastic anemia. Biochem Biophys Res Commun. 2014;454(1):102-108.
1114
MORIMOTO et al
22 FEBRUARY 2022 • VOLUME 6, NUMBER 4
Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1100/1870480/advancesadv2021005664.pdf by guest on 22 June 2022
15. Harigae H, Nakajima O, Suwabe N, et al. Aberrant iron accumulation and oxidized status of erythroid-specific delta-aminolevulinate synthase
(ALAS2)-deficient definitive erythroblasts. Blood. 2003;101(3):1188-1193.
...
論文の公開元へ
