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.

  • Brief Communication
  • Published:

Multiple myeloma gammopathies

Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients

Leukemia volume 33, pages 254–257 (2019)Cite this article

Subjects

A Correction to this article was published on 28 February 2019

This article has been updated

Systemic light chain (LC) amyloidosis (AL) is a protein misfolding disease in which a monoclonal immunoglobulin LC self-aggregates to form insoluble amyloid fibrils, which deposit in different organs and impairs the physiology of organs [1]. Researchers postulated that glycosylation also has a pathogenic effect on LCs and glycosylated LCs could be more prone to be amyloidogenic [2]. Pathogenic glycosylation of proteins has been implicated in various hematological malignancies, often with prognostic implications [3]. However, in comparison with other diseases, glycosylation of LCs has been relatively underinvestigated in AL. This is largely due to the lack of a high-throughput procedure to facilitate rapid analysis of LC glycosylation.

Previous studies using immuno-enrichment-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, demonstrated that M-protein mass distributions from AL patients often had an additional “polytypic-like” pattern along with the diagnostic monoclonal LC [4]. Further studies using high-resolution liquid chromatography-based MS (LC-MS) suggested that posttranslational modifications such as glycosylation on LCs could produce this “polytypic-like” pattern in AL patients [5]. Using MS approaches, we provide the most comprehensive mapping of LC glycosylation in AL reported to date.

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

Change history

  • 28 February 2019

    Following the publication of this article, the authors noted that Patrick M. Vanderboom was inadvertently omitted from the author list. The correct author list is as follows: Sanjay Kumar, David Murray, Surendra Dasari, Paolo Milani, David Barnidge, Benjamin Madden, Patrick M. Vanderboom, Taxiarchis Kourelis, Bonnie Arendt, Giampaolo Merlini, Marina Ramirez-Alvarado, Angela Dispenzieri. Patrick M. Vanderboom is affiliated with the Mayo Clinic in Rochester, MN.

  • 28 February 2019

    Following the publication of this article, the authors noted that Patrick M. Vanderboom was inadvertently omitted from the author list. The correct author list is as follows: Sanjay Kumar, David Murray, Surendra Dasari, Paolo Milani, David Barnidge, Benjamin Madden, Patrick M. Vanderboom, Taxiarchis Kourelis, Bonnie Arendt, Giampaolo Merlini, Marina Ramirez-Alvarado, Angela Dispenzieri. Patrick M. Vanderboom is affiliated with the Mayo Clinic in Rochester, MN.

References

  1. Kourelis TV, Dasari S, Theis JD, Ramirez-Alvarado M, Kurtin PJ, Gertz MA, et al. Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry. Blood. 2017;129:299–306.

    Article  CAS  Google Scholar 

  2. Bellotti V, Mangione P, Merlini G. Review: immunoglobulin light chain amyloidosis--the archetype of structural and pathogenic variability. J Struct Biol. 2000;130:280–9.

    Article  CAS  Google Scholar 

  3. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15:540–55.

    Article  CAS  Google Scholar 

  4. Milani P, Murray DL, Barnidge DR, Kohlhagen MC, Mills JR, Merlini G, et al. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol. 2017;92:772–9.

    Article  CAS  Google Scholar 

  5. Barnidge DR, Dispenzieri A, Merlini G, Katzmann JA, Murray DL. Monitoring free light chains in serum using mass spectrometry. Clin Chem Lab Med. 2016;54:1073–83.

    Article  CAS  Google Scholar 

  6. Kohlhagen MC, Barnidge DR, Mills JR, Stoner J, Gurtner KM, Liptac AM, et al. Screening method for M-proteins in serum using nanobody enrichment coupled to MALDI-TOF mass spectrometry. Clin Chem. 2016;62:1345–52.

    Article  CAS  Google Scholar 

  7. Dwulet FE, O’Connor TP, Benson MD. Polymorphism in a kappa I primary (AL) amyloid protein (BAN). Mol Immunol. 1986;23:73–8.

    Article  CAS  Google Scholar 

  8. Toft KG, Sletten K, Husby G. The amino-acid sequence of the variable region of a carbohydrate-containing amyloid fibril protein EPS (immunoglobulin light chain, type lambda). Biol Chem Hoppe Seyler. 1985;366:617–25.

    Article  CAS  Google Scholar 

  9. Stevens FJ. Four structural risk factors identify most fibril-forming kappa light chains. Amyloid. 2000;7:200–11.

    Article  CAS  Google Scholar 

  10. Dasari S, Theis JD, Vrana JA, Meureta OM, Quint PS, Muppa P, et al. Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies. J Proteome Res. 2015;14:1957–67.

    Article  CAS  Google Scholar 

  11. Connors LH, Jiang Y, Budnik M, Theberge R, Prokaeva T, Bodi KL, et al. Heterogeneity in primary structure, post-translational modifications, and germline gene usage of nine full-length amyloidogenic kappa1 immunoglobulin light chains. Biochemistry. 2007;46:14259–71.

    Article  CAS  Google Scholar 

  12. Sletten KWP, Husby G. Structural studies of the variable region of immunoglobulin light chain type amyloid fibril proteins. In: Glenner GGOE, Bendit EP, Calkins E, Cohen AS, Zucker-Franklin D, (ed). Amyloidosis. New York: Plennum Press; 1986. p. 463–75.

    Chapter  Google Scholar 

  13. Sox HC Jr., Hood L. Attachment of carbohydrate to the variable region of myeloma immunoglobulin light chains. Proc Natl Acad Sci USA. 1970;66:975–82.

    Article  CAS  Google Scholar 

  14. Ohkura T, Isobe T, Yamashita K, Kobata A. Structures of the carbohydrate moieties of two monoclonal human lambda-type immunoglobulin light chains. Biochemistry. 1985;24:503–8.

    Article  CAS  Google Scholar 

  15. Youings A, Chang SC, Dwek RA, Scragg IG. Site-specific glycosylation of human immunoglobulin G is altered in four rheumatoid arthritis patients. Biochem J. 1996;314(Pt 2):621–30.

    Article  Google Scholar 

Download references

Acknowledgements

We thank MeLea Hetrick and Mindy Kohlhagen for their help during experiments. This research was supported by Mayo Clinic, Rochester, MN, USA. This work was in part supported by the Predolin Foundation, the JABBS Foundation, a generous donation in the memory of Joey Bartzis, and by NIH grant CA125614.

Author contributions:

SK performed the experiments and drafted the manuscript. SK, AD, DLM, and SD designed, analyzed, interpreted the data, and edited the manuscript. BM performed the LC-MS experiments. PM had performed the experiments on the 154 patients from a prior report. TK and SD had performed the analyses of tissue amyloid as per a prior publication. Other authors contributed intellectual content and review of this manuscript.

Author information

Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Sanjay Kumar, Taxiarchis Kourelis & Angela Dispenzieri

  2. Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    David Murray, David Barnidge, Bonnie Arendt & Angela Dispenzieri

  3. Department of Health Science, Mayo Clinic, Rochester, MN, USA

    Surendra Dasari

  4. Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Paolo Milani & Giampaolo Merlini

  5. Medical Genomics Facility, Proteomics Core, Mayo Clinic, Rochester, MN, USA

    Benjamin Madden

  6. Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    Marina Ramirez-Alvarado

Authors
  1. Sanjay Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Surendra Dasari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Milani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Barnidge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Benjamin Madden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Taxiarchis Kourelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bonnie Arendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giampaolo Merlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marina Ramirez-Alvarado
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Angela Dispenzieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela Dispenzieri.

Ethics declarations

Conflict of interest

DLM and SD have financial interest in the MASS-FIX technology used in this study. All other authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, S., Murray, D., Dasari, S. et al. Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients. Leukemia 33, 254–257 (2019). https://doi.org/10.1038/s41375-018-0194-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0194-x

This article is cited by

Search

Advanced search

Quick links