The mutation status of genes involved in the NF-κB signaling pathway in splenic marginal zone lymphoma was examined. DNA sequence analysis of four genes was performed: CD79A, CD79B, CARD11, and MYD88 that are activated through BCR signaling or Toll-like and interleukin signaling. A single point mutation was detected in the CD79B gene (Y196H) in one of ten SMZL cases. Additionally, one point mutation was identified in the MYD88 gene (L265P) in another SMZL case. No mutations were revealed in CD79A or CARD11 genes in these SMZL cases. Neither were mutations detected in these four genes studied in 13 control MZL samples. Interestingly, the two cases with mutations of CD79B and MYD88 showed increased numbers of immunoblasts spread among the smaller and typical marginal zone lymphoma cells. Although SMZL shows few mutations of NF-κB signaling genes, our results indicate that the presence of these mutations is associated with a higher histological grade. 1. Introduction Marginal zone lymphoma (MZL) is a non-Hodgkin lymphoma that likely develops from B-lymphocytes in the marginal zone of secondary lymphoid tissue. There are three subtypes of marginal zone B-cell lymphoma (MZL) [1]: nodal, extranodal, and splenic marginal zone lymphoma, arising in the lymph node, mucosa, and the spleen, respectively. Splenic marginal zone lymphoma (SMZL) is an indolent, low grade B-cell lymphoma primarily characterized by splenomegaly with variable involvement of lymph nodes, bone marrow, peripheral blood, and other organs. It accounts for less than 1% of non-Hodgkin lymphoma [2]. The normal splenic marginal zone contains both memory B cells and naive B cells. In parallel, unmutated as well as mutated immunoglobulin heavy chain genes are found [3–5]. Gene expression profiling has revealed aberrant NF-κB signaling in several lymphoma types such as diffuse large B-cell lymphoma (DLBCL) [6, 7], Hodgkin lymphoma [8], and SMZL [9]. NF-κB is a transcription factor that regulates different cellular processes, such as cell growth and survival [10] and is activated when normal B-cells respond to antigen. In one subtype of DLBCL, of activated B-cell origin (ABC), NF-κB signaling is constitutively activated due to mutations of important B-cell receptor (BCR) signaling genes [11]. These include mutations of the gene for caspase recruitment domain-containing protein 11 (CARD11) in 10% [12] and mutations and/or deletions of CD79, an essential signaling subunit of the BCR in 21% of ABC DLBCL [13]. Of interest, Ngo et al. have described oncogenic MYD88 mutations [14]. MyD88 is an adaptor
References
[1]
S. H. Swerdlow, E. Campo, N. L. Harris et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Lyon, France, 4th edition, 2008.
[2]
B. Kahl and D. Yang, “Marginal zone lymphomas: management of nodal, splenic, and MALT NHL,” Hematology, vol. 2008, no. 1, pp. 359–364, 2008.
[3]
P. Algara, M. S. Mateo, M. Sanchez-Beato et al., “Analysis of the IgV(H) somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course,” Blood, vol. 99, no. 4, pp. 1299–1304, 2002.
[4]
C. Kalpadakis, G. A. Pangalis, E. Dimitriadou et al., “Mutation analysis of IgVH genes in splenic marginal zone lymphomas: correlation with clinical characteristics and outcome,” Anticancer Research, vol. 29, no. 5, pp. 1811–1816, 2009.
[5]
K. Stamatopoulos, C. Belessi, T. Papadaki et al., “Immunoglobulin heavy- and light-chain repertoire in splenic marginal zone lymphoma,” Molecular Medicine, vol. 10, no. 7–12, pp. 89–95, 2004.
[6]
A. A. Alizadeh, M. B. Eisen, R. E. Davis et al., “Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling,” Nature, vol. 403, no. 6769, pp. 503–511, 2000.
[7]
R. E. Davis, K. D. Brown, U. Siebenlist, and L. M. Staudt, “Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells,” Journal of Experimental Medicine, vol. 194, no. 12, pp. 1861–1874, 2001.
[8]
R. Küppers, U. Klein, I. Schwering et al., “Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling,” The Journal of Clinical Investigation, vol. 111, no. 4, pp. 529–537, 2003.
[9]
E. Ruiz-Ballesteros, M. Mollejo, A. Rodriguez et al., “Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis,” Blood, vol. 106, no. 5, pp. 1831–1838, 2005.
[10]
P. J. Jost and J. Ruland, “Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications,” Blood, vol. 109, no. 7, pp. 2700–2707, 2007.
[11]
M. Compagno, W. K. Lim, A. Grunn et al., “Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma,” Nature, vol. 459, no. 7247, pp. 717–721, 2009.
[12]
G. Lenz, R. E. Davis, V. N. Ngo et al., “Oncogenic CARD11 mutations in human diffuse large B cell lymphoma,” Science, vol. 319, no. 5870, pp. 1676–1679, 2008.
[13]
R. E. Davis, V. N. Ngo, G. Lenz, et al., “Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma,” Nature, vol. 463, pp. 88–92, 2010.
[14]
V. N. Ngo, R. M. Young, R. Schmitz et al., “Oncogenically active MYD88 mutations in human lymphoma,” Nature, vol. 470, no. 7332, pp. 115–119, 2011.
[15]
D. Rossi, S. Deaglio, D. Dominguez-Sola, et al., “Alteration of BIRC3 and multiple other NF-{kappa}B pathway genes in splenic marginal zone lymphoma,” Blood, vol. 118, no. 18, pp. 4930–4934, 2011.
[16]
Y. Yan, Y. Huang, A. J. Watkins, et al., “BCR and TLR signalling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas,” Haematologica, vol. 97, no. 4, pp. 595–598, 2012.
[17]
U. Novak, A. Rinaldi, I. Kwee et al., “The NF-κB negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas,” Blood, vol. 113, no. 20, pp. 4918–4921, 2009.
