Increased ferroptosis of erythrocytes is associated with myelodysplastic syndromes.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 9107334 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0584 (Electronic) Linking ISSN: 09395555 NLM ISO Abbreviation: Ann Hematol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin ; New York : Springer International, c1991-

Ferroptosis* ; Myelodysplastic Syndromes*/pathology ; Myelodysplastic Syndromes*/metabolism ; Myelodysplastic Syndromes*/blood ; Myelodysplastic Syndromes*/complications; Humans ; Female ; Male ; Middle Aged ; Aged ; Erythrocytes/metabolism ; Erythrocytes/pathology ; Lipid Peroxidation ; Anemia/pathology ; Anemia/etiology ; Anemia/blood ; Adult ; Aged, 80 and over ; Iron/metabolism ; Iron/blood

Anemia is the most common symptom in patients with myelodysplastic syndromes (MDS). Programmed cell death of erythrocytes is one of the contributing factors to anemia. Ferroptosis is a newly identified form of iron-dependent cell death. The aim of this study is to investigate whether anemia in MDS patients is associated with ferroptosis of nucleated erythrocytes(NEs).We detected lipid peroxidation levels, Fe ²⁺ contents, cell death rates, glutathione (GSH) and malondialdehyde (MDA) levels in bone marrow CD235a ⁺ NEs of MDS patients. Expression levels of ferroptosis-related molecules (ACSL4, GPX4, and SLC7A11) were evaluated through qRT-PCR and Western Blotting. Correlation between these markers and clinical parameters were analyzed. To further substantiate that the mode of cell death with CD235a ⁺ NEs of MDS patients was attributed to the ferroptosis pathway, we applied Fer-1 to inhibit ferroptosis. Cell viability was assessed using CCK8, and changes in ferroptosis-related indicators were simultaneously evaluated. We discover that the ferroptosis level of bone marrow NEs in MDS patients was increased, which is related to anemia and iron overload. Ferroptosis might be one of the causes of anemia in MDS patients.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405. (PMID: 10.1182/blood-2016-03-64354427069254)
Cazzola M (2020) Myelodysplastic syndromes. N Engl J Med 383(14):1358–1374. (PMID: 10.1056/NEJMra190479432997910)
Tefferi A, Vardiman JW (2009) Myelodysplastic syndromes. N Engl J Med 361(19):1872–1885. (PMID: 10.1056/NEJMra090290819890130)
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ et al (2017) Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biology, and Disease. Cell 171(2):273–285. (PMID: 10.1016/j.cell.2017.09.021289855605685180)
Cao JY, Dixon SJ (2016) Mechanisms of ferroptosis. Cell Mol Life Sci 73(11–12): 2195 – 209.
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F et al (2014) Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A 111(47):16836–16841. (PMID: 10.1073/pnas.1415518111253856004250130)
Tang D, Chen X, Kang R, Kroemer G (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125. (PMID: 10.1038/s41422-020-00441-133268902)
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. (PMID: 10.1016/j.cell.2012.03.042226329703367386)
Probst L, Dächert J, Schenk B, Fulda S (2017) Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. Biochem Pharmacol 140:41–52. (PMID: 10.1016/j.bcp.2017.06.11228595877)
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1–2):317–331. (PMID: 10.1016/j.cell.2013.12.010244393854076414)
Hartmann J, Braulke F, Sinzig U, Wulf G, Maas JH, Konietschke F, Haase D (2013) Iron overload impairs proliferation of erythroid progenitors cells(BFU-E) from patients with myelodysplastic syndromes. Leuk Res 37(3):327–332. (PMID: 10.1016/j.leukres.2012.11.00523259989)
Cui R, Gale RP, Zhu G, Xu Z, Qin T, Zhang Y et al (2014) Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. Leuk Res 38(5):545–550. (PMID: 10.1016/j.leukres.2014.01.016245988414439195)
Chen Z, Jiang J, Fu N, Chen L (2022) Targetting ferroptosis for blood cell-related diseases. J Drug Target 30(3):244–258. (PMID: 10.1080/1061186X.2021.197123734415804)
Lv Q, Niu H, Yue L, Liu J, Yang L, Liu C, Jiang H, Dong S, Shao Z, Xing L, Wang H (2020) Abnormal ferroptosis in Myelodysplastic Syndrome. Front Oncol 10:1656. (PMID: 10.3389/fonc.2020.01656329840387492296)
Garcia-Manero G (2023) Myelodysplastic syndromes:2023 update on diagnosis,risk-stratification, and management. Am J Hematol 98(8):1307–1325. (PMID: 10.1002/ajh.2698437288607)
Greenberg PL, Attar E, Bennett JM, Bloomfield CD, Borate U, De Castro CM et al (2011) NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. J Natl Compr Canc Netw 9(1):30–56. (PMID: 10.6004/jnccn.2011.0005212332433768131)
Zhao J, Jia Y, Mahmut D, Deik AA, Jeanfavre S, Clish CB, Sankaran VG (2023) Human hematopoietic stem cell vulnerability to ferroptosis. Cell 186(4):732–747e16. (PMID: 10.1016/j.cell.2023.01.020368036039978939)
Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282. (PMID: 10.1038/s41580-020-00324-8334956518142022)
Cadet J, Davies K, Medeiros MH, Di Mascio P, Wagner JR (2017) Formation and repair of oxidatively generated damage in cellular DNA. Free Radic Biol Med 107:13–34. (PMID: 10.1016/j.freeradbiomed.2016.12.049280576005457722)
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D (2016) Ferroptosis: process and function. Cell Death Differ 23(3):369–379. (PMID: 10.1038/cdd.2015.158267944435072448)
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523. (PMID: 10.7554/eLife.02523248442464054777)
Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):88. (PMID: 10.1038/s41419-020-2298-2320153256997353)
Yang WS, Stockwell BR (2008) Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234–245. (PMID: 10.1016/j.chembiol.2008.02.010183557232683762)
Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26(3):165–176. (PMID: 10.1016/j.tcb.2015.10.01426653790)
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191. (PMID: 10.1038/ncb306425402683)
Hirschhorn T, Stockwell BR (2019) The development of the concept of ferroptosis. Free Radic Biol Med 133:130–143. (PMID: 10.1016/j.freeradbiomed.2018.09.04330268886)
Yuan H, Li X, Zhang X, Kang R, Tang D (2016) Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 478(3):1338–1343. (PMID: 10.1016/j.bbrc.2016.08.12427565726)
Słomka A, Pokrzywa A, Strzała D, Kubiaczyk M, Wesolowska O, Denkiewicz K et al (2024) The role of Hepcidin in Myelodysplastic syndromes(MDS): a systematic review of Observational studies. Cancers(Basel) 16(2):332. (PMID: 38254820)
Gonçalves AC, Cortesão E, Oliveiros B, Alves V, Espadana AI, Rito L et al (2015) Oxidative stress and mitochondrial dysfunction play a role in myelodysplastic syndrome development, diagnosis, and prognosis: a pilot study. Free Radic Res 49(9):1081–1094. (PMID: 10.3109/10715762.2015.103526825968944)
Mitchell M, Gore SD, Zeidan AM (2013) Iron chelation therapy in myelodysplastic syndromes: where do we stand. Expert Rev Hematol 6(4):397–410. (PMID: 10.1586/17474086.2013.814456239919264124619)
Petzer V, Theurl I, Weiss G, Wolf D (2021) EnvlRONmental aspects in Myelodysplastic Syndrome. Int J Mol Sci 22(10):5202. (PMID: 10.3390/ijms22105202340689968156755)
Gattermann N, Finelli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A et al (2012) Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica 97(9):1364–1371. (PMID: 10.3324/haematol.2011.048546224195773436237)
Nolte F, Höchsmann B, Giagounidis A, Lübbert M, Platzbecker U, Haase D et al (2013) Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload. Ann Hematol 92(2):191–198. (PMID: 10.1007/s00277-012-1594-z23073603)
Gattermann N (2018) Iron overload in myelodysplastic syndromes(MDS). Int J Hematol 107(1):55–63. (PMID: 10.1007/s12185-017-2367-129177643)
Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz EA (2010) Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica 95(8):1433–1434. (PMID: 10.3324/haematol.2010.024992204212742913096)
Canli Ö, Alankuş YB, Grootjans S, Vegi N, Hültner L, Hoppe PS, Schroeder T, Vandenabeele P, Bornkamm GW, Greten FR (2016) Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood 127(1):139–148. (PMID: 10.1182/blood-2015-06-654194264634244705604)

18ZXDBSY00140 Key Technology Research and Development Program of Tianjin China; ZYYFY2018026 The Zhao Yi-Cheng Medical Science Foundation; 2022KJ235 Educational Commission of Tianjin China; 14JCYBJC27200, 09JCYBJC11200 Application Bases and Advanced Technology Research Program of Tianjin China; 82270139, 81170472 The National Natural Science Foundation of China

Keywords: Anemia; Erythrocytes; Ferroptosis; Myelodysplastic syndromes

E1UOL152H7 (Iron)

Date Created: 20240823 Date Completed: 20241026 Latest Revision: 20241026

20241027

10.1007/s00277-024-05946-y

39177794