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Keywords:

  • MALT lymphoma;
  • oncogenes;
  • MYD88 ;
  • NF-KB;
  • new drugs for lymphoma

Extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue type (MALT lymphoma) is an indolent lymphoma that is found at a number of different extranodal anatomical sites and in total accounts for 7–8% of all non-Hodgkin (Bertoni et al, 2011). Recurrent chromosomal translocations and unbalanced genomic aberrations have been reported in MALT, many of which lead to activation of the nuclear factor (NF)-κB pathway (Bertoni et al, 2011). MYD88 is a central molecule in the cascade that activates NF-κB signalling after stimulation of either Toll-like, interleukin (IL) 1 and IL18 receptors (Ngo et al, 2011). The MYD88 gene is located at chromosome 3p22, a region commonly gained in MALT lymphomas (Rinaldi et al, 2011). MYD88 mutations were first described to occur almost exclusively in the activated B-cell like subtype (39%) of diffuse large B-cell lymphomas (Ngo et al, 2011), which are also characterized by NF-κB activation. Recurrent mutations were also described in 9% of gastric MALT lymphomas (Ngo et al, 2011). The vast majority of mutations, and all those observed in MALT lymphomas, determined a non-synonymous change at amino acid position 265 with a change from leucine to proline (L265P) (Ngo et al, 2011). Very recently, Xu et al (2011) identified the same MYD88 L265P change in 46/51 (90%) lymphoplasmacytic lymphomas (LPL), 87% with an IgM monoclonal protein (Waldenstrom Macroglobulinemia, WM), contrasting with 3/46 (6%) in MZLs, including 1/20 (5%) MALT lymphomas (Xu et al, 2011). These authors suggested that a L265P mutation could be used to differentiate LPL/WM from MZLs (Xu et al, 2011).

With the aim of assessing the prevalence of MYD88 L265P mutations in MALT lymphomas, we studied 53 MALT lymphoma cases, previously characterized by genome-wide DNA profiling (Rinaldi et al, 2011). Informed consent was obtained in accordance with the Declaration of Helsinki following the procedures approved by the local ethical committees and institutional review boards of each participating institution. Whole genome-amplification (WGA) was performed as previously described (Mensah et al, 2012). MYD88 exon 5 underwent polymerase chain reaction (PCR) amplification using 5′-AGG GAG GACT GTG GAT GCA GTA CCA A -3′ and 5′-CTG CAG ACG TGT CTG TGA AGT T-3′, as forward and reverse primers (Morin et al, 2011), respectively. PCR products were sequenced as previously described (Mensah et al, 2012), and the sequence chromatograms were viewed with ChromasLite 2.01 (Technelysium Pty Ltd, Brisbane, Qld, Australia) and compared against GenBank NM_002468.

Three out of the 53 (6%) of the MALT lymphoma cases revealed non-synonymous MYD88 mutations, all of which were verified using non-WGA DNA (Fig 1). Two cases harboured a T978C mutation causing the reported L265P substitution. Both of these cases presented with orbital adnexa involvement and no additional genomic lesions; one case had bone marrow involvement. One case of salivary gland MALT lymphoma, with trisomies of chromosomes 3 and 18, showed a novel interstitial 27bp deletion (c.1039_1065del) resulting in the loss of amino acids VCDYTNPCT (p.V286_T294del) that precede an internal inhibitory domain (Li et al, 2005; Ngo et al, 2011), which could become disrupted and allow an increased binding of MYD88 to IRAK1/IRAK4. Somatic mutations of MYD88 have been shown to activate down-stream signalling leading to the activation of both NF-κB but also JAK/STAT3 signalling (Ngo et al, 2011), providing a rationale for molecule-targeted pharmaceutical approaches in these patients.

image

Figure 1. MYD88 mutations in MALT lymphomas. Upper panel, chromatograms of MYD88 exon 5 highlighting the identified two DNA point mutations and the start of the 27-bp long interstitial deletion. Lower panel, three-dimensional structure of the MYD88 TIR domain (PDB 2JS7), with the L265P mutation highlighted in purple, and the novel deletion of nine amino-acids highlighted in red.

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In conclusion, our data indicate that MYD88 is deregulated in a small subset of patients with MALT lymphoma. These MYD88 mutation-bearing patients, as well patients affected by LPL/WM (Xu et al, 2011) or by other indolent lymphoid tumours carrying similar mutations (Fabbri et al, 2011; Wang et al, 2011; Yan et al, 2012) will benefit from the development of new therapeutic strategies that target specific pathways irrespective of the lymphoma subtype.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. Authors contribution
  4. Conflict of interest
  5. References

This work was supported by Oncosuisse grant OCS-02034-02-2007, Nelia and Amedeo Barletta Foundation (Lausanne, Switzerland) and Italian Association for Cancer Research (AIRC).

Authors contribution

  1. Top of page
  2. Acknowledgements
  3. Authors contribution
  4. Conflict of interest
  5. References

FB conceived and designed the study. ZML, AR, AC and AAM performed analyses. MP, RDG, GB and EZ collected and characterized MZL samples. ZML, AC and FB interpreted the data and co-wrote the manuscript.

Conflict of interest

  1. Top of page
  2. Acknowledgements
  3. Authors contribution
  4. Conflict of interest
  5. References

All authors read and approved the final manuscript. All authors declare no conflict of interest.

References

  1. Top of page
  2. Acknowledgements
  3. Authors contribution
  4. Conflict of interest
  5. References
  • Bertoni, F., Coiffier, B., Salles, G., Stathis, A., Traverse-Glehen, A., Thieblemont, C. & Zucca, E. (2011) MALT lymphomas: pathogenesis can drive treatment. Oncology (Williston Park), 25, 11341142, 1147.
  • Fabbri, G., Rasi, S., Rossi, D., Trifonov, V., Khiabanian, H., Ma, J., Grunn, A., Fangazio, M., Capello, D., Monti, S., Cresta, S., Gargiulo, E., Forconi, F., Guarini, A., Arcaini, L., Paulli, M., Laurenti, L., Larocca, L.M., Marasca, R., Gattei, V., Oscier, D., Bertoni, F., Mullighan, C.G., Foa, R., Pasqualucci, L., Rabadan, R., Dalla-Favera, R. & Gaidano, G. (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. Journal of Experimental Medicine, 208, 13891401.
  • Li, C., Zienkiewicz, J. & Hawiger, J. (2005) Interactive sites in the MyD88 Toll/Interleukin (IL) 1 receptor domain responsible for coupling to the IL1β signaling pathway. Journal of Biological Chemistry, 280, 2615226159.
  • Mensah, A.A., Rinaldi, A., Ponzoni, M., Canzonieri, V., Uccella, S., Rossi, D., Bhagat, G., Gaidano, G., Zucca, E. & Bertoni, F. (2012) Absence of NOTCH1 gene mutations in MALT lymphomas. British Journal of Haematology, 157, 382384.
  • Morin, R.D., Mendez-Lago, M., Mungall, A.J., Goya, R., Mungall, K.L., Corbett, R.D., Johnson, N.A., Severson, T.M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., Scott, D.W., Trinh, D.L., Tamura-Wells, J., Li, S., Firme, M.R., Rogic, S., Griffith, M., Chan, S., Yakovenko, O., Meyer, I.M., Zhao, E.Y., Smailus, D., Moksa, M., Chittaranjan, S., Rimsza, L., Brooks-Wilson, A., Spinelli, J.J., Ben-Neriah, S., Meissner, B., Woolcock, B., Boyle, M., McDonald, H., Tam, A., Zhao, Y., Delaney, A., Zeng, T., Tse, K., Butterfield, Y., Birol, I., Holt, R., Schein, J., Horsman, D.E., Moore, R., Jones, S.J., Connors, J.M., Hirst, M., Gascoyne, R.D. & Marra, M.A. (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature, 476, 298303.
  • Ngo, V.N., Young, R.M., Schmitz, R., Jhavar, S., Xiao, W., Lim, K.H., Kohlhammer, H., Xu, W., Yang, Y., Zhao, H., Shaffer, A.L., Romesser, P., Wright, G., Powell, J., Rosenwald, A., Muller-Hermelink, H.K., Ott, G., Gascoyne, R.D., Connors, J.M., Rimsza, L.M., Campo, E., Jaffe, E.S., Delabie, J., Smeland, E.B., Fisher, R.I., Braziel, R.M., Tubbs, R.R., Cook, J.R., Weisenburger, D.D., Chan, W.C. & Staudt, L.M. (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature, 470, 115119.
  • Rinaldi, A., Mian, M., Chigrinova, E., Arcaini, L., Bhagat, G., Novak, U., Rancoita, P.M., De Campos, C.P., Forconi, F., Gascoyne, R.D., Facchetti, F., Ponzoni, M., Govi, S., Ferreri, A.J., Mollejo, M., Piris, M.A., Baldini, L., Soulier, J., Thieblemont, C., Canzonieri, V., Gattei, V., Marasca, R., Franceschetti, S., Gaidano, G., Tucci, A., Uccella, S., Tibiletti, M.G., Dirnhofer, S., Tripodo, C., Doglioni, C., Dalla Favera, R., Cavalli, F., Zucca, E., Kwee, I. & Bertoni, F. (2011) Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome. Blood, 117, 15951604.
  • Wang, L., Lawrence, M.S., Wan, Y., Stojanov, P., Sougnez, C., Stevenson, K., Werner, L., Sivachenko, A., DeLuca, D.S., Zhang, L., Zhang, W., Vartanov, A.R., Fernandes, S.M., Goldstein, N.R., Folco, E.G., Cibulskis, K., Tesar, B., Sievers, Q.L., Shefler, E., Gabriel, S., Hacohen, N., Reed, R., Meyerson, M., Golub, T.R., Lander, E.S., Neuberg, D., Brown, J.R., Getz, G. & Wu, C.J. (2011) SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. New England Journal of Medicine, 365, 24972506.
  • Xu, L., Sohani, A.R., Arcaini, L., Hunter, Z., Yang, G., Zhou, Y., Liu, X., Cao, Y., Manning, R., Patterson, C.J., Ioakimidis, L., Tripsas, C., Pinkus, G.S., Harris, N.L., Rodig, S.J. & Treon, S. (2011) A somatic variant in MYD88 (L265P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas. Blood (ASH Annual Meeting Abstracts), 118, 261.
  • Yan, Y., Huang, Y., Watkins, A.J., Kocialkowski, S., Zeng, N., Hamoudi, R.A., Isaacson, P.G., de Leval, L., Wotherspoon, A. & Du, M.Q. (2012) BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. Haematologica, 97, 595598.