International Journal of Hematology

, Volume 106, Issue 2, pp 248–257 | Cite as

Iron overload may promote alteration of NK cells and hematopoietic stem/progenitor cells by JNK and P38 pathway in myelodysplastic syndromes

  • Yanni Hua
  • Chaomeng Wang
  • Huijuan Jiang
  • Yihao Wang
  • Chunyan Liu
  • Lijuan Li
  • Hui Liu
  • Zonghong Shao
  • Rong Fu
Original Article


The objective of the study was to examine levels of intracellular iron, reactive oxygen species (ROS) and the expression of JNK and p38MAPK in NK cells and hematopoietic stem/progenitor cells (HSPCs) in MDS patients, and explore potential mechanisms by which iron overload (IOL) promotes MDS progression. Thirty-four cases of MDS and six cases of AML transformed from MDS (MDS/AML) were included. HSPCs and NK cells were isolated by magnetic absorption cell sorting. We used flow cytometry to detect the levels of ROS and intracellular JNK and P38 in NK cells and HSPCs. Total RNA and protein were extracted from NK cells and CD34+ cells to examine the expression of JNK and p38MAPK using RT-PCR and Western blotting. Intracellular iron concentration was detected. Data were analyzed by SPSS 21 statistical software. Intracellular iron concentration and ROS were increased in both NK cells and HSPCs in MDS patients with iron overload (P < 0.05). MDS patients with iron overload had higher JNK expression and lower p38 expression in NK cells, and higher p38 expression in HSPCs compared with non-iron overload group. IOL may cause alterations in NK cells and HSPCs through the JNK and p38 pathways, and play a role in the transformation to AML from MDS.


Myelodysplastic syndromes Iron overload JNK P38MAPK 



Yanni Hua, Chaomeng Wang, Huijuan Jiang, Yihao Wang, Chunyan Liu, Lijuan Li, Hui Liu, Zonghong Shao, and Rong Fu, all from the Department of Hematology, Tianjin Medical University General Hospital, made contributions to the manuscript. All authors agreed to the content of the manuscript and its submission to IJH.

Compliance with ethical standards

Conflict of interest

All authors have no financial relationship with any organization that sponsored the research. The authors declare no conflicts of interest.


  1. 1.
    Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23:7594–603.CrossRefPubMedGoogle Scholar
  2. 2.
    Cazzola M, Malcovati L. Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Takatoku M, Uchiyama T, Okamoto S, Kanakura Y, Sawada K, Tomonaga M, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007;78:487–94.CrossRefPubMedGoogle Scholar
  4. 4.
    Goldberg SL, Chen E, Corral M, Guo A, Mody-Patel N, Pecora AL, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol. 2010;28:2847–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Lyons RM, Marek BJ, Paley C, Esposito J, Garbo L, DiBella N, et al. Comparison of 24-month outcomes in chelated and non-chelated lower-risk patients with myelodysplastic syndromes in a prospective registry. Leuk Res. 2014;38:149–54.CrossRefPubMedGoogle Scholar
  6. 6.
    Delforge M, Selleslag D, Beguin Y, Triffet A, Mineur P, Theunissen K, et al. Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk Res. 2014;38:557–63.CrossRefPubMedGoogle Scholar
  7. 7.
    Lee JH, Khor TO, Shu L, Su ZY, Fuentes F, Kong AN, et al. Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther. 2013;137:153–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Pearson G, Robinson F, Gibson TB, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–83.PubMedGoogle Scholar
  9. 9.
    Gattermann N, Rachmilewitz EA. Iron overload in MDS-pathophysiology, diagnosis, and complications. Ann Hematol. 2011;90:1–10.CrossRefPubMedGoogle Scholar
  10. 10.
    Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies). Leuk Res. 2010;34:864–70.CrossRefPubMedGoogle Scholar
  11. 11.
    Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, et al. Reduced natural killer (NK) function associated with high–risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–24.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mi H, Fu R, Wang H, Qu W, Ruan E, Wang X, et al. Changes of natural kill cell in peripheral blood of patients with myelodysplastic syndrome. Zhonghua Yi Xue Za Zhi. 2014;94:737–41.PubMedGoogle Scholar
  13. 13.
    Chinese Society of Hematology/Chinese Medical Doctor Association, Hematology Branch. A Chinese expert panel consensus statement on diagnosis and treatment of iron overload. Chin J Hematol. 2011;32:572–4.Google Scholar
  14. 14.
    Antosiewicz J, Ziolkowski W, Kaczor JJ, Herman-Antosiewicz A. Tumor necrosis factor-alpha-induced reactive oxygen species formation is mediated by JNK1-dependent ferritin degradation and elevation of labile iron pool. Free Radic Biol Med. 2007;43:265–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Deb S, Johnson EE, Robalinho-Teixeira RL, Wessling-Resnick M. Modulation of intracellular iron levels by oxidative stress implicates a novel role for iron in signal transduction. Biometals. 2009;22:855–62.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jian J, Yang Q, Dai J, Eckard J, Axelrod D, Smith J, et al. Effects of iron deficiency and overload on angiogenesis and oxidative stress -a potential dual role for iron in breast cancer. Free Radic Biol Med. 2011;50:841–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Yu Y, Richardson DR. Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1. J Biol Med. 2011;286:15413–27.Google Scholar
  18. 18.
    Cherayil BJ. Iron and immunity: immunological consequences of iron deficiency and overload. Arch Immunol Ther Exp (Warsz). 2010;58:407–15.CrossRefGoogle Scholar
  19. 19.
    Teng DH, Perry WL 3rd, Hogan JK, Baumgard M, Bell R, Berry S, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 1997;57:4177–82.PubMedGoogle Scholar
  20. 20.
    Finegan KG, Tournier C. The mitogen-activated protein kinase kinase 4 has a pro-oncogenic role in skin cancer. Cancer Res. 2010;70:5797–806.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Huang C, Huang K, Wang C, Jiang ZD, Li XX, Wang HP, et al. Overexpression of mitogen-activated protein kinase kinase 4 and nuclear factor-kappaB in laryngeal squamous cell carcinoma: a potential indicator for poor prognosis. Oncol Rep. 2009;22:89–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 2000;14:2147–57.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Yanni Hua
    • 1
  • Chaomeng Wang
    • 1
  • Huijuan Jiang
    • 1
  • Yihao Wang
    • 1
  • Chunyan Liu
    • 1
  • Lijuan Li
    • 1
  • Hui Liu
    • 1
  • Zonghong Shao
    • 1
  • Rong Fu
    • 1
  1. 1.Department of HematologyTianjin Medical University General HospitalTianjinPeople’s Republic of China

Personalised recommendations