Abstract
Myocyte enhancer binding factor 2 B (MEF2B) is a member of the evolutionary conserved transcription family MEF2. MEF2B has been shown to directly control biological activity of the B cell lymphoma 6 (BCL6) gene in germinal center (GC) B cells. To validate MEF2B as an immunohistochemical marker, we studied a large consecutive series of hyperplastic lymphoid tissues (n = 38) and malignant lymphoproliferative conditions (n = 471), including all major categories of B and T cell neoplasms. In hyperplastic lymphoid tissues, MEF2B staining revealed intense and crisp nuclear expression confined to GC B cells. Unlike BCL6, MEF2B was not detected in follicular T cells. In addition, weak nuclear staining of plasma cells was noted. MEF2B staining labeled neoplastic cells of follicular lymphoma both in common and variant cases as well as in bone marrow biopsies with high sensitivity, while it was almost consistently negative in marginal zone lymphoma. Consistent MEF2B expression was found in Burkitt lymphoma and nodular lymphocyte predominant Hodgkin lymphoma as well as in the large majority of cases of mantle cell lymphoma and diffuse large cell B cell lymphoma. MEF2B protein expression showed a statistically significant association with that of BCL6 in cases of diffuse large B cell lymphoma, not otherwise specified. We conclude that MEF2B is a valuable marker of normal GC B cells, potentially useful in differential diagnosis of small B cell lymphomas.
Similar content being viewed by others
References
Yu YT, Breitbart RE, Smoot LB, Lee Y, Mahdavi V, Nadal-Ginard B (1992) Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev 6:1783–1798. doi:10.1101/gad.6.9.1783
JC MD, Cardoso MC, Yu Y-T, et al (1993) hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors. Mol Cell Biol 13:2564–2577
Olson EN, Perry M, Schulz RA (1995) Regulation of muscle differentiation by the MEF1 family of MADS box transcription factors. Dev Biol 172:2–14. doi:10.1006/dbio.1995.0002
Potthoff MJ, Olson EN (2007) MEF2: a central regulator of diverse developmental programs. Development 134:4131–4140. doi:10.1242/dev.008367
Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME (1999) Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286:785–790. doi:10.1126/science.286.5440.785
Black BL, Olson EN (1998) Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 14:167–196. doi:10.1146/annurev.cellbio.14.1.167
TA MK, Zhang CL, Olson EN (2002) MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci 27:40–47
Han A, Pan F, Stroud JC, Youn HD, Liu JO, Chen L (2003) Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2. Nature 422:730–734. doi:10.1038/nature01555
Cheng LE, Chan FK, Cado D, Winoto A (1997) Functional redundancy of the Nur77 and Nor-1orphan steroid receptors in T-cell apoptosis. EMBO J 16:1865–1875. doi:10.1093/emboj/16.8.1865
Swanson BJ, Jack HM, Lyons GE (1998) Characterization of myocyte enhancer binding factor 2 (MEF2) expression in B and T cells: MEF2C is a B cell restricted transcription factor in lymphocytes. Mol Immun. 35:445–458
Youn HD, Sun L, Prywes R, Liu JO (1999) Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science 286:790–793. doi:10.1126/science.286.5440.790
Khiem D, Cyster JG, Schwarz JJ, Black BL (2008) A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proc Natl Acad Sci U S A 105:17067–17072. doi:10.1073/pnas.0804868105
Molkentin JD, Firulli AB, Black BL, et al. (1996) MEF2B is a potent transactivator expressed in early myogenic lineages. Mol Cell Biol 16:3814–3824
Ying CY, Dominguez-Sola D, Fabi M, et al (2013) MEF2B mutations lead to deregulated expression of the oncogene bcl-6 in diffuse large B cell lymphoma. Nat Immunol 14:1084–1092. doi:10.1038/ni.2688
Swerdlow SH, Campo E, Harris NL, et al (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon
Hans CP, Weisenburger DD, Greiner T, et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282. doi:10.1182/blood-2003-05-1545
Harris NL, Swerdlow SH, Jaffe ES, et al (2008) Follicular lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 220–226
Eshoa C, Perkins S, Kampalath B, Shidham V, Juckett M, Chang CC (2001) Decreased CD10 expression in grade III and in interfollicular infiltrates of follicular lymphomas. Am J Clin Pathol 115:862–867
Ott G, Katzenberger T, Lohr A, et al (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 99:3806–3812. doi:10.1182/blood.V99.10.3806
Willemze R, Swerdlow SH, Harris NL, Vergier B (2008) Primary cutaneous follicle centre lymphoma. Follicular lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 227–228
Dogan A, Du DQ, Aiello A, et al (1998) Follicular lymphomas contain a clonally linked but phenotypically distinct neoplastic B-cell population in the interfollicular zone. Blood 91:4708–4714
Younes SF, Beck AH, Lossos IS, Levy R, Warnke RA, Natkunam Y (2010) Immunoarchitectural patterns in follicular lymphoma: efficacy of HGAL and LMO2 in the detection of the interfollicular and diffuse components. Am J Surg Pathol 34:1266–1276. doi:10.1097/PAS.0b013e3181e9343d
Katzenberger T, Kalla J, Leich E, et al (2009) A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood 113:1053–1061. doi:10.1182/blood-2008-07-168682
West RB, Warnke RA, Natkunaam Y (2002) The usefulness of immunohistochemistry in the diagnosis of follicular lymphoma in bone marrow biopsy specimens. Am J Clin Pathol 117:636–643
Younes SF, Beck AH, Ohgami RS, et al (2011) The efficacy of HGAL and LMO2 in the separation of lymphomas derived from small B cells in nodal and extranodal sites, including the bone marrow. Am J Clin Pathol 135:697–708. doi:10.1309/AJCP7Z2BIBUNQPLZ
Morin RD, Mendez-Lago M, Mungall AJ, et al (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476:298–303. doi:10.1038/nature10351
Banks PM, Chan J, Cleary ML, et al (1992) Mantle cell lymphoma. A proposal for unification of morphologic, immologic, and molecular data. Am J Surg Pathol 16:637–640
Swerdlow SH, Campo E, Seto M, Müller-Hermelink HK (2008) Mantle cell lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 229–232
Bea S, Valdes-Mas R, Navarro A, et al (2013) Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A 110:18250–18255. doi:10.1073/pnas.1314608110
Zanetto U, Dong H, Huang Y, et al (2008) Mantle cell lymphoma with aberrant expression of CD10. Histopathology 53:20–29. doi:10.1111/j.1365-2559.2008.03060.x
Gualco G, Weiss LM, Harrington Jr WJ, Bacchi CE (2010) BCL6, MUM1, and CD10 expression in mantle cell lymphoma. Appl Immunohistochem Mol Morphol 18:103–108. doi:10.1097/PAI.0b013e3181bb9edf
Agostinelli C, Paterson JC, Gupta R, et al (2012) Detection of LIM domain only 2 (LMO2) in normal human tissues and haematopoietic and non-haematopoietic tumours using a newly developed rabbit monoclonal antibody. Histopathology 61:33–46. doi:10.1111/j.1365-2559.2012.04198.x
Isaacson PG, Piris MA, Berger F, et al (2008) Splenic B-cell marginal zone lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 185–187
Isaacson PG, Chot A, Nakamura S, Müller-Hermelink HK, Harris NL, Swerdlow SH (2008) Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma). In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 214–217
Campo E, Pileri SA, Jaffe ES, Müller-Hermelink HK, Nathwani BN Nodal marginal zone lymphoma. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon. pp 218–219
Salama ME, Lossos IS, Warnke RA, Natkunam Y (2009) Immunoarchitectural patterns in nodal marginal zone B-cell lymphoma: a study of 51 cases. Am J Clin Pathol 132:39–49. doi:10.1309/AJCPZQ1GXBBNG8OG
Pasqualucci L, Trifonov V, Fabbri G, et al (2011) Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43:830–837. doi:10.1038/ng.892
Lohr JG, Stojanov P, Lawrence MS, et al (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 109:3879–3884. doi:10.1073/pnas.1121343109
Zhang J, Grubor V, Love CL, et al (2013) Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 110:1398–1403. doi:10.1073/pnas.1205299110
Basso K, Dalla-Favera R (2012) Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev 247:172–183. doi:10.1111/j.1600-065X.2012.01112.x
Stein H, Warnke RA, Chan WC, et al (2008) Diffuse large B-cell lymphoma, not otherwise specified. In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, WHO classification of tumours, vol 2, 4th edn. IARC Press, Lyon, pp. 233–237
Alizadeh AA, Eisen MB, Davis RE, et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511. doi:10.1038/35000501
Choi WW, Weisenburger DD, Greiner TC, et al (2009) A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 15:5494–5502. doi:10.1158/1078-0432.CCR-09-0113
Braeuninger A, Kuppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML (1997) Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 94:9337–9342
Acknowledgments
We thank Ágnes Dudás and Hedvig Dósa for their excellent technical contribution. We are grateful to Giovanna Roncador for providing us the PD1/NAT105C monoclonal antibody. This research was in part supported by the Social Renewal Operational Program of the Hungarian Government-TÁMOP-4.2.2.A-11/1/KONV-2012–0045 project.
Conflict of interest
The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Krenács, D., Borbényi, Z., Bedekovics, J. et al. Pattern of MEF2B expression in lymphoid tissues and in malignant lymphomas. Virchows Arch 467, 345–355 (2015). https://doi.org/10.1007/s00428-015-1796-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-015-1796-6