Annals of Hematology

, Volume 97, Issue 3, pp 475–484 | Cite as

Unraveling the heterogeneity of IgM monoclonal gammopathies: a gene mutational and gene expression study

  • Cristina Jiménez
  • María Isabel Prieto-Conde
  • María García-Álvarez
  • Miguel Alcoceba
  • Fernando Escalante
  • María del Carmen Chillón
  • Alfonso García de Coca
  • Ana Balanzategui
  • Alberto Cantalapiedra
  • Carlos Aguilar
  • Rocío Corral
  • Tomás González-López
  • Luis A. Marín
  • Abelardo Bárez
  • Noemí Puig
  • Aránzazu García-Mateo
  • Norma C. Gutiérrez
  • María Eugenia Sarasquete
  • Marcos GonzálezEmail author
  • Ramón García-Sanz
Original Article


Immunoglobulin M (IgM) monoclonal gammopathies show considerable variability, involving three different stages of presentation: IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), asymptomatic Waldenström’s macroglobulinemia (AWM), and symptomatic WM (SWM). Despite recent findings about the genomic and transcriptomic characteristics of such disorders, we know little about the causes of this clinical heterogeneity or the mechanisms involved in the progression from indolent to symptomatic forms. To clarify these matters, we have performed a gene expression and mutational study in a well-characterized cohort of 69 patients, distinguishing between the three disease presentations in an attempt to establish the relationship with the clinical and biological features of the patients. Results showed that the frequency of genetic alterations progressively increased from IgM-MGUS to AWM and SWM. This means that, in contrast to MYD88 p.L265P and CXCR4 WHIM mutations, present from the beginning of the pathogenesis, most of them would be acquired during the course of the disease. Moreover, the expression study revealed a higher level of expression of genes belonging to the Toll-like receptor (TLR) signaling pathway in symptomatic versus indolent forms, which was also reflected in the disease presentation and prognosis. In conclusion, our findings showed that IgM monoclonal gammopathies present higher mutational burden as the disease progresses, in parallel to the upregulation of relevant pathogenic pathways. This study provides a translational view of the genomic basis of WM pathogenesis.


IgM monoclonal gammopathies Heterogeneity Mutations Gene expression Clinicobiological features 


Author contributions

C.J. and R.G.S. designed the initial study and selected the patients. C.J., M.I.P.C., and M.G.A. processed the samples and carried out all the molecular studies. C.J., A.B., M.C.C., and M.E.S. collected and analyzed the data and interpreted the results. R.G.S. and M.A. designed and helped manage the database. R.G.S., R.C., and L.A.M. supervised the statistical analysis.

R.G.S., F.E., A.G.C., A.C., C.A., T.G.L., A.B., and A.G.M. were the clinicians responsible for the patients, ensuring the protocols were correctly followed, sampling, and collecting clinical data.

N.P. and N.C.G. were responsible for the immunophenotyping and cytogenetic analysis, respectively, of the patients included in this series.

C.J. prepared the initial version of the paper. R.G.S. reviewed the conception and design of most of the work and corrected the manuscript. M.G., the head of the group, supervised the final revision of the draft and gave final approval for the version to be published.

Financial support

This work was supported by research grants from the Gerencia Regional de Salud (GRS 847/A/13), the Asociación Castellano-Leonesa de Hematología y Hemoterapia (FUCALHH 2015), and the Gilead Sciences (GILEAD) Fellowship Program (GLD16/00162), as well as funds from the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, CIBERONC-CB16/12/00233.

Compliance with ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008, and informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2017_3207_MOESM1_ESM.docx (18 kb)
Supplemental Table 1 (DOCX 17 kb)
277_2017_3207_MOESM2_ESM.docx (19 kb)
Supplemental Table 2 (DOCX 19 kb)
277_2017_3207_MOESM3_ESM.docx (15 kb)
Supplemental Table 3 (DOCX 14 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Cristina Jiménez
    • 1
  • María Isabel Prieto-Conde
    • 1
  • María García-Álvarez
    • 1
  • Miguel Alcoceba
    • 1
    • 2
  • Fernando Escalante
    • 3
  • María del Carmen Chillón
    • 1
    • 2
  • Alfonso García de Coca
    • 4
  • Ana Balanzategui
    • 1
  • Alberto Cantalapiedra
    • 5
  • Carlos Aguilar
    • 6
  • Rocío Corral
    • 1
  • Tomás González-López
    • 7
  • Luis A. Marín
    • 1
  • Abelardo Bárez
    • 8
  • Noemí Puig
    • 1
  • Aránzazu García-Mateo
    • 9
  • Norma C. Gutiérrez
    • 1
  • María Eugenia Sarasquete
    • 1
    • 2
  • Marcos González
    • 1
    • 2
    Email author
  • Ramón García-Sanz
    • 1
    • 2
  1. 1.Hematology DepartmentUniversity Hospital of Salamanca and Research Biomedical Institute of Salamanca (IBSAL)SalamancaSpain
  2. 2.Center for Biomedical Research in Network of Cancer (CIBERONC)SalamancaSpain
  3. 3.Hematology DepartmentHospital Complex of LeónLeónSpain
  4. 4.Hematology DepartmentUniversity Clinical Hospital of ValladolidValladolidSpain
  5. 5.Hematology DepartmentRío Hortega University HospitalValladolidSpain
  6. 6.Hematology DepartmentSanta Bárbara HospitalSoriaSpain
  7. 7.Hematology DepartmentHospital Complex of BurgosBurgosSpain
  8. 8.Hematology DepartmentNuestra Señora de Sonsoles HospitalÁvilaSpain
  9. 9.Hematology DepartmentGeneral Hospital of SegoviaSegoviaSpain

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