Advertisement

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

Abstract

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.

Keywords

IgM monoclonal gammopathies Heterogeneity Mutations Gene expression Clinicobiological features 

Notes

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)

References

  1. 1.
    Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA (2003) Clinicopathological definition of Waldenström’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 30(2):110–115.  https://doi.org/10.1053/sonc.2003.50082 CrossRefPubMedGoogle Scholar
  2. 2.
    Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd (2003) Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood 102(10):3759–3764.  https://doi.org/10.1182/blood-2003-03-0801
  3. 3.
    Kyle RA, Dispenzieri A, Kumar S, Larson D, Therneau T, Rajkumar SV (2011) IgM monoclonal gammopathy of undetermined significance (MGUS) and smoldering Waldenström’s macroglobulinemia (SWM). Clin Lymphoma Myeloma Leuk 11(1):74–76.  https://doi.org/10.3816/CLML.2011.n.011 CrossRefPubMedGoogle Scholar
  4. 4.
    Kyle RA, Benson JT, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Melton LJ, Rajkumar SV (2012) Progression in smoldering Waldenström’s macroglobulinemia: long-term results. Blood 119(19):4462–4466.  https://doi.org/10.1182/blood-2011-10-384768 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR (2012) MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 367(9):826–833.  https://doi.org/10.1056/NEJMoa1200710 CrossRefPubMedGoogle Scholar
  6. 6.
    Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X, Morra E, Trojani A, Greco A, Arcaini L, Varettoni M, Brown JR, Tai YT, Anderson KC, Munshi NC, Patterson CJ, Manning RJ, Tripsas CK, Lindeman NI, Treon SP (2013) MYD88 L265P in Waldenstrom’s macroglobulinemia, IgM monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific PCR. Blood 121(11):2051–2058.  https://doi.org/10.1182/blood-2012-09-454355 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jiménez C, Sebastián E, Chillón MC, Giraldo P, Mariano Hernández J, Escalante F, González-López TJ, Aguilera C, de Coca AG, Murillo I, Alcoceba M, Balanzategui A, Sarasquete ME, Corral R, Marín LA, Paiva B, Ocio EM, Gutiérrez NC, González M, San Miguel JF, García-Sanz R (2013) MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia 27(8):1722–1728.  https://doi.org/10.1038/leu.2013.62 CrossRefPubMedGoogle Scholar
  8. 8.
    Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP (2014) The genomic landscape of Waldenström macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 123(11):1637–1646.  https://doi.org/10.1182/blood-2013-09-525808 CrossRefPubMedGoogle Scholar
  9. 9.
    Roccaro AM, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, Aljawai Y, Sahin I, Kuhne M, Cardarelli P, Cohen L, San Miguel JF, Garcia-Sanz R, Ghobrial IM (2014) C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 123(26):4120–4131.  https://doi.org/10.1182/blood-2014-03-564583 CrossRefPubMedGoogle Scholar
  10. 10.
    Xu L, Hunter ZR, Tsakmaklis N, Cao Y, Yang G, Chen J, Liu X, Kanan S, Castillo JJ, Tai YT, Zehnder JL, Brown JR, Carrasco RD, Advani R, Sabile JM, Argyropoulos K, Lia Palomba M, Morra E, Trojani A, Greco A, Tedeschi A, Varettoni M, Arcaini L, Munshi NM, Anderson KC, Treon SP (2016) Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia. Br J Haematol 172(5):735–744.  https://doi.org/10.1111/bjh.13897 CrossRefPubMedGoogle Scholar
  11. 11.
    Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR (2014) Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenström macroglobulinemia. Blood 123(18):2791–2796.  https://doi.org/10.1182/blood-2014-01-550905 CrossRefPubMedGoogle Scholar
  12. 12.
    Braggio E, Keats JJ, Leleu X, van Wier S, Jimenez-Zepeda VH, Valdez R, Schop RFJ, Price-Troska T, Henderson K, Sacco A, Azab F, Greipp P, Gertz M, Hayman S, Rajkumar SV, Carpten J, Chesi M, Barrett M, Stewart AK, Dogan A, Bergsagel PL, Ghobrial IM, Fonseca R (2009) Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kB signaling pathways in Waldenström’s macroglobulinemia. Cancer Res 69(8):3579–3588.  https://doi.org/10.1158/0008-5472.CAN-08-3701 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Poulain S, Roumier C, Galiègue-Zouitina S, Daudignon A, Herbaux C, Aiijou R, Lainelle A, Broucqsault N, Bertrand E, Manier S, Renneville A, Soenen V, Tricot S, Roche-Lestienne C, Duthilleul P, Preudhomme C, Quesnel B, Morel P, Leleu X (2013) Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia. Am J Hematol 88(11):948–954.  https://doi.org/10.1002/ajh.23545 CrossRefPubMedGoogle Scholar
  14. 14.
    Draghici S, Khatri P, Eklund AC, Szallasi Z (2006) Reliability and reproducibility issues in DNA microarray measurements. Trends Genet 22(2):101–109.  https://doi.org/10.1016/j.tig.2005.12.005 CrossRefPubMedGoogle Scholar
  15. 15.
    Kothapalli R, Yoder SJ, Mane S, Loughran TP (2002) Microarray results: how accurate are they? BMC Bioinform 3(1):22.  https://doi.org/10.1186/1471-2105-3-22 CrossRefGoogle Scholar
  16. 16.
    Bergsagel PL, Kuehl WM (2005) Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23(26):6333–6338.  https://doi.org/10.1200/JCO.2005.05.021 CrossRefPubMedGoogle Scholar
  17. 17.
    Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, Bertsch U, Buijs A, Stevens-Kroef M, Beverloo HB, Vellenga E, Zweegman S, Kersten MJ, van der Holt B, el Jarari L, Mulligan G, Goldschmidt H, van Duin M, Sonneveld P (2010) Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 116(14):2543–2553.  https://doi.org/10.1182/blood-2009-12-261032 CrossRefPubMedGoogle Scholar
  18. 18.
    Chng WJ, Schop RF, Price-Troska T, Ghobrial I, Kay N, Jelinek DF, Gertz MA, Dispenzieri A, Lacy M, Kyle RA, Greipp PR, Tschumper RC, Fonseca R, Bergsagel PL (2006) Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 108(8):2755–2763.  https://doi.org/10.1182/blood-2006-02-005488 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gutiérrez N, Ocio E, de las Rivas J et al (2007) Gene expression profiling of B lymphocytes and plasma cells from Waldenström’s macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 21(3):541–549.  https://doi.org/10.1038/sj.leu.2404520 CrossRefPubMedGoogle Scholar
  20. 20.
    Leleu X, Hunter ZR, Xu L, Roccaro AM, Moreau AS, Santos DD, Hatjiharissi E, Bakthavachalam V, Adamia S, Ho AW, Soumerai J, Patterson CJ, Manning RJ, Hamilton S, Verselis S, Fox E, Carrasco R, Ghobrial IM, Treon SP (2009) Expression of regulatory genes for lymphoplasmacytic cell differentiation in Waldenstrom Macroglobulinemia. Br J Haematol 145(1):59–63.  https://doi.org/10.1111/j.1365-2141.2009.07592.x CrossRefPubMedGoogle Scholar
  21. 21.
    Hunter ZR, Xu L, Yang G, Tsakmaklis N, Vos JM, Liu X, Chen J, Manning RJ, Chen JG, Brodsky P, Patterson CJ, Gustine J, Dubeau T, Castillo JJ, Anderson KC, Munshi NM, Treon SP (2016) Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood 128(6):827–838.  https://doi.org/10.1182/blood-2016-03-708263 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Poulain S, Roumier C, Venet-Caillault A, Figeac M, Herbaux C, Marot G, Doye E, Bertrand E, Geffroy S, Lepretre F, Nibourel O, Decambron A, Boyle EM, Renneville A, Tricot S, Daudignon A, Quesnel B, Duthilleul P, Preudhomme C, Leleu X (2016) Genomic landscape of CXCR4 mutations in Waldenström macroglobulinemia. Clin Cancer Res 22(6):1480–1488.  https://doi.org/10.1158/1078-0432.CCR-15-0646 CrossRefPubMedGoogle Scholar
  23. 23.
    Trojani A, Greco A, Tedeschi A, Lodola M, di Camillo B, Ricci F, Turrini M, Varettoni M, Rattotti S, Morra E (2013) Microarray demonstrates different gene expression profiling signatures between waldenström macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. Clin Lymphoma, Myeloma Leuk 13(2):208–210.  https://doi.org/10.1016/j.clml.2013.02.012 CrossRefGoogle Scholar
  24. 24.
    Paiva B, Corchete LA, Vidriales M-B, Garcia-Sanz R, Perez JJ, Aires-Mejia I, Sanchez ML, Barcena P, Alignani D, Jimenez C, Sarasquete ME, Mateos MV, Ocio EM, Puig N, Escalante F, Hernandez J, Cuello R, Garcia de Coca A, Sierra M, Montes MC, Gonzalez-Lopez TJ, Galende J, Barez A, Alonso J, Pardal E, Orfao A, Gutierrez NC, San Miguel JF (2015) The cellular origin and malignant transformation of Waldenstrom macroglobulinemia. Blood 125(15):2370–2380.  https://doi.org/10.1182/blood-2014-09-602565 CrossRefPubMedGoogle Scholar
  25. 25.
    Herbaux C, Bertrand E, Marot G, Roumier C, Poret N, Soenen V, Nibourel O, Roche-Lestienne C, Broucqsault N, Galiègue-Zouitina S, Boyle EM, Fouquet G, Renneville A, Tricot S, Morschhauser F, Preudhomme C, Quesnel B, Poulain S, Leleu X (2016) BACH2 promotes indolent clinical presentation in Waldenström macroglobulinemia. Oncotarget.  https://doi.org/10.18632/oncotarget.9917
  26. 26.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (2008) World Health Organization classification of tumours of haematopoietic and lymphoid tissues. IARC Press, LyonGoogle Scholar
  27. 27.
    Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117(19):5019–5032.  https://doi.org/10.1182/blood-2011-01-293050 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jiménez C, Chillón Mdel C, Balanzategui A, Puig N, Sebastián E, Alcoceba M, Sarasquete ME, Conde IP, Corral R, Marín LA, Paiva B, Ruano M, Antón A, Maldonado R, San Miguel JF, González M, García-Sanz R (2014) Detection of MYD88 L265P mutation by real-time allele-specific oligonucleotide polymerase chain reaction. Appl Immunohistochem Mol Morphol 22(10):768–773.  https://doi.org/10.1097/PAI.0000000000000020
  29. 29.
    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25(14):1754–1760.  https://doi.org/10.1093/bioinformatics/btp324 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303.  https://doi.org/10.1101/gr.107524.110 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ocio EM, del CD, Caballero Á et al (2011) Differential diagnosis of IgM MGUS and WM according to B-lymphoid infiltration by morphology and flow cytometry. Clin Lymphoma Myeloma Leuk 11(1):93–95.  https://doi.org/10.3816/CLML.2011.n.017 CrossRefPubMedGoogle Scholar
  32. 32.
    Paiva B, Montes MC, García-Sanz R, Ocio EM, Alonso J, de las Heras N, Escalante F, Cuello R, de Coca AG, Galende J, Hernández J, Sierra M, Martin A, Pardal E, Bárez A, Alonso J, Suarez L, González-López TJ, Perez JJ, Orfao A, Vidríales MB, San Miguel JF (2014) Multiparameter flow cytometry for the identification of the Waldenström’s clone in IgM-MGUS and Waldenström’s Macroglobulinemia: new criteria for differential diagnosis and risk stratification. Leukemia 28(1):166–173.  https://doi.org/10.1038/leu.2013.124 CrossRefPubMedGoogle Scholar
  33. 33.
    Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, Dalva K, Fuhler G, Gratama J, Hose D, Kovarova L, Lioznov M, Mateo G, Morilla R, Mylin AK, Omede P, Pellat-Deceunynck C, Andres MP, Petrucci M, Ruggeri M, Rymkiewicz G, Schmitz A, Schreder M, Seynaeve C, Spacek M, de Tute RM, van Valckenborgh E, Weston-Bell N, Owen RG, San Miguel JF, Sonneveld P, Johnsen HE, on behalf of the European Myeloma Network (2008) Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica 93(3):431–438.  https://doi.org/10.3324/haematol.11080 CrossRefPubMedGoogle Scholar
  34. 34.
    van Dongen JJM, Lhermitte L, Böttcher S et al (2012) EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 26(9):1908–1975.  https://doi.org/10.1038/leu.2012.120 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Pedreira CE, Costa ES, Almeida J, Fernandez C, Quijano S, Flores J, Barrena S, Lecrevisse Q, van Dongen JJM, Orfao A, on behalf of the EuroFlow Consortium (2008) A probabilistic approach for the evaluation of minimal residual disease by multiparameter flow cytometry in leukemic B-cell chronic lymphoproliferative disorders. Cytometry A 73A(12):1141–1150.  https://doi.org/10.1002/cyto.a.20638 CrossRefPubMedGoogle Scholar
  36. 36.
    Ocio EM, Hernandez JM, Mateo G et al (2005) Immunophenotypic and cytogenetic comparison of Waldenstrom’s macroglobulinemia with splenic marginal zone lymphoma. Clin Lymphoma 5(4):241–245.  https://doi.org/10.3816/CLM.2005.n.007 CrossRefPubMedGoogle Scholar
  37. 37.
    Ngo HT, Leleu X, Lee J, Jia X, Melhem M, Runnels J, Moreau AS, Burwick N, Azab AK, Roccaro A, Azab F, Sacco A, Farag M, Sackstein R, Ghobrial IM (2008) SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. Blood 112(1):150–158.  https://doi.org/10.1182/blood-2007-12-129395 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    García-Sanz R (2016) WM, MYD88, and CXCR4: following the thread. Blood 128(6):746–748.  https://doi.org/10.1182/blood-2016-06-722462 CrossRefPubMedGoogle Scholar
  39. 39.
    Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R (2011) Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43(9):830–837.  https://doi.org/10.1038/ng.892 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang J, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463(7277):88–92.  https://doi.org/10.1038/nature08638 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Argyropoulos K, Vogel R, Ziegler C et al (2016) Clonal B cells in Waldenström’s macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia 30(5):1116–1125.  https://doi.org/10.1038/leu.2016.8 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, García-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C, iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia (2017) Ibrutinib for patients with rituximab-refractory Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 18(2):241–250.  https://doi.org/10.1016/S1470-2045(16)30632-5 CrossRefPubMedGoogle Scholar
  43. 43.
    Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Hernandez-Lemus E, Schwarz-Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR (2012) Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 109(10):3879–3884.  https://doi.org/10.1073/pnas.1121343109 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, Scott DW, Ding J, Roth A, Chiu R, Corbett RD, Chan FC, Mendez-Lago M, Trinh DL, Bolger-Munro M, Taylor G, Hadj Khodabakhshi A, Ben-Neriah S, Pon J, Meissner B, Woolcock B, Farnoud N, Rogic S, Lim EL, Johnson NA, Shah S, Jones S, Steidl C, Holt R, Birol I, Moore R, Connors JM, Gascoyne RD, Marra MA (2013) Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122(7):1256–1265.  https://doi.org/10.1182/blood-2013-02-483727 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, Patterson CJ, Buhrlage SJ, Gray N, Tai YT, Anderson KC, Hunter ZR, Treon SP (2013) A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood 122(7):1222–1232.  https://doi.org/10.1182/blood-2012-12-475111 CrossRefPubMedGoogle Scholar

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

Personalised recommendations