Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MYELODYSPLASTIC SYNDROME

Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms

Leukemia volume 36, pages 2086–2096 (2022)Cite this article

Subjects

Abstract

Myeloperoxidase (MPO) gene alterations with variable clinical penetrance have been found in hereditary MPO deficiency, but their leukemia association in patients and carriers has not been established. Germline MPO alterations were found to be significantly enriched in myeloid neoplasms: 28 pathogenic/likely pathogenic variants were identified in 100 patients. The most common alterations were c.2031-2 A > C, R569W, M519fs* and Y173C accounting for about half of the cases. While functional experiments showed that the marrow stem cell pool of Mpo−/− mice was not increased, using competitive repopulation demonstrated that Mpo−/− grafts gained growth advantage over MPO wild type cells. This finding also correlated with increased clonogenic potential after serial replating in the setting of H2O2-induced oxidative stress. Furthermore, we demonstrated that H2O2-induced DNA damage and activation of error-prone DNA repair may result in secondary genetic damage potentially predisposing to leukemia leukemic evolution. In conclusion, our study for the first time demonstrates that germline MPO variants may constitute risk alleles for MN evolution.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Allelic imbalance and characteristics of germline MPO alterations among myeloid malignancies and bone marrow failure syndromes.
Fig. 2: Loss of function Mpo mutations gain proliferative advantage over wild-type competitors and increase clonogenic potential after exposure to peroxide treatment.
Fig. 3: Human myeloperoxidase levels, activities and H2O2 release from human leukemia cells.
Fig. 4: Apoptosis assay of HL-60 and K562, treated with H2O2 500 µM and with/without MPOi for 24 h (A) and 48 h (B) before analysis.
Fig. 5: Phospho-Ɣ-H2AX, the DNA damage/repair marker, detection by flow cytometry. HL-60 and K562 were treated with H2O2 200 µM and with/without MPOi.

Similar content being viewed by others

References

  1. Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013;27:19–41.

    Article  PubMed  Google Scholar 

  2. Li ST, Wang J, Wei R, Shi R, Adema V, Nagata Y, et al. Rare germline variant contributions to myeloid malignancy susceptibility. Leukemia. 2020;34:1675–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Morishita K, Kubota N, Asano S, Kaziro Y, Nagata S. Molecular cloning and characterization of cDNA for human myeloperoxidase. J Biol Chem. 1987;262:3844–51.

    Article  CAS  PubMed  Google Scholar 

  4. Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77:598–625.

    Article  CAS  PubMed  Google Scholar 

  5. Nauseef WM. Myeloperoxidase in human neutrophil host defence. Cell Microbiol. 2014;16:1146–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11:519–31.

    Article  CAS  PubMed  Google Scholar 

  7. Pahwa R, Modi P, Jialal I Myeloperoxidase Deficiency. StatPearls. StatPearls Publishing Copyright © 2021, StatPearls Publishing LLC.: Treasure Island (FL), 2021.

  8. Marchetti C, Patriarca P, Solero GP, Baralle FE, Romano M. Genetic studies on myeloperoxidase deficiency in Italy. Jpn J Infect Dis. 2004;57:S10–12.

    PubMed  Google Scholar 

  9. Endo D, Saito T, Umeki Y, Suzuki K, Aratani Y. Myeloperoxidase negatively regulates the expression of proinflammatory cytokines and chemokines by zymosan-induced mouse neutrophils. Inflamm Res. 2016;65:151–9.

    Article  CAS  PubMed  Google Scholar 

  10. Milla C, Yang S, Cornfield DN, Brennan ML, Hazen SL, Panoskaltsis-Mortari A, et al. Myeloperoxidase deficiency enhances inflammation after allogeneic marrow transplantation. Am J Physiol Lung Cell Mol Physiol. 2004;287:L706–714.

    Article  CAS  PubMed  Google Scholar 

  11. Kremserova S, Perecko T, Soucek K, Klinke A, Baldus S, Eiserich JP, et al. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation. Oxid Med Cell Longev. 2016;2016:5219056.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005;25:1102–11.

    Article  CAS  PubMed  Google Scholar 

  13. Strzepa A, Pritchard KA, Dittel BN. Myeloperoxidase: A new player in autoimmunity. Cell Immunol. 2017;317:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Malle E, Buch T, Grone HJ. Myeloperoxidase in kidney disease. Kidney Int. 2003;64:1956–67.

    Article  CAS  PubMed  Google Scholar 

  15. Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A. Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit? Acta Haematol. 2000;104:10–15.

    Article  CAS  PubMed  Google Scholar 

  16. Pfeilstöcker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Solé F, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016;128:902–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013;45:942–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nagata Y, Makishima H, Kerr CM, Przychodzen BP, Aly M, Goyal A, et al. Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes. Nat Commun. 2019;10:5386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hirsch CM, Nazha A, Kneen K, Abazeed ME, Meggendorfer M, Przychodzen BP, et al. Consequences of mutant TET2 on clonality and subclonal hierarchy. Leukemia. 2018;32:1751–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49:204–12.

    Article  CAS  PubMed  Google Scholar 

  21. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74:5463–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nauseef WM, Cogley M, Bock S, Petrides PE. Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation. J Leukoc Biol. 1998;63:264–9.

    Article  CAS  PubMed  Google Scholar 

  24. DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest. 1998;101:2900–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Romano M, Dri P, Da Dalt L, Patriarca P, Baralle FE. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood. 1997;90:4126–34.

    Article  CAS  PubMed  Google Scholar 

  26. Lanza F, Fietta A, Spisani S, Castoldi GL, Traniello S. Does a relationship exist between neutrophil myeloperoxidase deficiency and the occurrence of neoplasms? J Clin Lab Immunol. 1987;22:175–80.

    CAS  PubMed  Google Scholar 

  27. Cappelletti P, Lippi U. Hereditary myeloperoxidase deficiency: a rare condition? Diagnostic possibilities of a differential white cell autoanalyzer (Hemalog-D). Haematologica. 1983;68:736–41.

    CAS  PubMed  Google Scholar 

  28. Lanza F. Clinical manifestation of myeloperoxidase deficiency. J Mol Med (Berl). 1998;76:676–81.

    Article  CAS  Google Scholar 

  29. Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci USA. 2009;106:1187–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Awan A, Malcolm Taylor G, Gokhale DA, Dearden SP. Increased Frequency of Fanconi Anemia Group C Genetic Variants in Children With Sporadic Acute Myeloid Leukemia. Blood. 1998;91:4813–4.

    Article  CAS  PubMed  Google Scholar 

  31. Berwick M, Satagopan JM, Ben-Porat L, Carlson A, Mah K, Henry R, et al. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007;67:9591–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rao S, Yao Y, Soares de Brito J, Yao Q, Shen AH, Watkinson RE, et al. Dissecting ELANE neutropenia pathogenicity by human HSC gene editing. Cell Stem Cell. 2021;28:833–45. 2021/05/06/e835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat. 2013;34:905–14.

    Article  CAS  PubMed  Google Scholar 

  34. Rydzynska Z, Pawlik B, Krzyzanowski D, Mlynarski W, Madzio J. Neutrophil Elastase Defects in Congenital Neutropenia. Front. Immunol. 2021;12:1–12.

  35. Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, et al. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood. 2014;123:2229–37.

    Article  CAS  PubMed  Google Scholar 

  36. Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood. 2007;109:93–99.

    Article  CAS  PubMed  Google Scholar 

  37. Kettle AJ, Winterbourn CC. Myeloperoxidase: a key regulator of neutrophil oxidant production. Redox Rep. 1997;3:3–15.

    Article  CAS  PubMed  Google Scholar 

  38. Rosales C, Lowell CA, Schnoor M, Uribe-Querol E. Neutrophils: Their role in innate and adaptive immunity 2017. J Immunol Res. 2017;2017:9748345.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Burdon RH. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med. 1995;18:775–94.

    Article  CAS  PubMed  Google Scholar 

  40. Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB, et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem. 1997;272:217–21.

    Article  CAS  PubMed  Google Scholar 

  41. Hansberg W, Aguirre J. Hyperoxidant states cause microbial cell differentiation by cell isolation from dioxygen. J Theor Biol. 1990;142:201–21.

    Article  CAS  PubMed  Google Scholar 

  42. Arnold RS, Shi J, Murad E, Whalen AM, Sun CQ, Polavarapu R, et al. Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci USA. 2001;98:5550–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994;15:7–10.

    Article  CAS  PubMed  Google Scholar 

  44. Forman HJ, Bernardo A, Davies KJ. What is the concentration of hydrogen peroxide in blood and plasma? Arch Biochem Biophys. 2016;603:48–53.

    Article  CAS  PubMed  Google Scholar 

  45. Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol. 2017;11:613–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Valverde M, Lozano-Salgado J, Fortini P, Rodriguez-Sastre MA, Rojas E, Dogliotti E. Hydrogen Peroxide-Induced DNA Damage and Repair through the Differentiation of Human Adipose-Derived Mesenchymal Stem Cells. Stem Cells Int. 2018;2018:1615497.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Driessens N, Versteyhe S, Ghaddhab C, Burniat A, De Deken X, Van Sande J, et al. Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ. Endocr Relat Cancer. 2009;16:845–56.

    Article  CAS  PubMed  Google Scholar 

  48. McDonald RJ, Pan LC, St George JA, Hyde DM, Ducore JM. Hydrogen peroxide induces DNA single strand breaks in respiratory epithelial cells. Inflammation. 1993;17:715–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in parts by grants from NIH (R35HL135795 and RO1 HL132071 to JPM and R01 CA257544-01A1 to BKJ). We thank the Vera and Joseph Dresner Foundation (to VV) and the American Italian Cancer Foundation (to CG).

Author information

Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Sunisa Kongkiatkamon, Laila Terkawi, Yihong Guan, Vera Adema, Metis Hasipek, Milo Co, Hassan Awada, Yvonne Parker, Simona Pagliuca, Carmelo Gurnari, Daniel J. Lindner, Valeria Visconte, Babal K. Jha & Jaroslaw P. Maciejewski

  2. Research Unit in Translational Hematology, Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Sunisa Kongkiatkamon

  3. Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    Tatiana Dombrovski & Thomas LaFramboise

  4. MLL Munich Leukemia Laboratory, Munich, Germany

    Wencke Walter, Stephan Hutter, Manja Meggendorfer & Torsten Haferlach

  5. Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA

    Heesun J. Rogers

Authors
  1. Sunisa Kongkiatkamon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laila Terkawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yihong Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vera Adema
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Metis Hasipek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatiana Dombrovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Milo Co
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wencke Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hassan Awada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yvonne Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephan Hutter
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Simona Pagliuca
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carmelo Gurnari
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Heesun J. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Manja Meggendorfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Daniel J. Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Torsten Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Valeria Visconte
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Thomas LaFramboise
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Babal K. Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jaroslaw P. Maciejewski
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SK, designed research studies, performed experiments, acquired data, analyzed data, and wrote the draft manuscript. LT., MC performed flow cytometry analysis, collected clinical specimens, and performed Sanger sequencing; VA analyzed RNA sequencing; WW processed raw data of RNA-sequencing; ST analyzed raw data of genomic sequencing; HA collected clinical data and interpreted sequencing data; CG provided and interpreted clinical data and wrote the manuscript; SP provided insights on statistical analysis and data interpretation and wrote the manuscript. YG, MH, TD, contributed with reagents and discussed the design. VV, helped, designed and supervised mouse experiments, data analysis, discussed the results, and wrote manuscript. HJR, reviewed bone marrow histopathology. TL help and perform data analysis. DL and YP helped with mouse experiments and edited the manuscript. MM, TH provided genomic data. BKJ conceived and conceptualize the idea, designed, and supervised the research, acquired, and discussed the results. JPM conceived and conceptualization, read and edited the manuscript and generated resources. All authors read and edited the manuscript.

Corresponding author

Correspondence to Jaroslaw P. Maciejewski.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kongkiatkamon, S., Terkawi, L., Guan, Y. et al. Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms. Leukemia 36, 2086–2096 (2022). https://doi.org/10.1038/s41375-022-01630-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01630-0

Search

Advanced search

Quick links