Synonym: Interferon Regulatory Factor 4 (IRF4) (PIP, LSIRT, ICSAT, NFEMS). Nature: Nuclear transcription factor necessary for development and activation of B lymphocytes. MUM1 belongs to the IRF gene family containing at least 10 widely expressed genes with similar DNA binding motif all involved in regulation of cell growth, transformation and induction of apoptosis as well as development of T-cell immune response. Gene and structure: 19p13.3, 51.6 kDa. Occurrence and function: MUM1 plays an important role in the regulation of gene expression in response to interferon and other cytokines. MUM1 is a gene primarily identified in Multiple Myeloma cell line where it was localized in region of chromosomal translocations t(6;14)(p25;q32) placing this gene in proximity of IgH enhancer locus. Expression is also important for the differentiation of monocytes along macrophage and dendritic cell pathways. The expression of MUM1 protein appears at the later stages of B-cell differentiation after the expression of CD10 and Bcl-6. B-lymphocytes in light zone of germinal centers (late stage of germinal center differentiation) and post-germinal lymphocytes are generally positive. The expression of MUM1 and Bcl-6 in normal germinal center B cells appears to be mutually exclusive. MUM1 is constantly found at all stages of differentiation of plasma cells. Nuclear expression is present also in a subpopulation of activated T- lymphocytes. MUM1 protein is furthermore expressed in normal and neoplastic melanocytes but not found in other cell types. Some oncogenic viruses (HTLV-I and EBV), activate the NF-?B pathway and consequently elevate MUM1/IRF4 expression. Abnormalities: The MUM1/IFR4 gene deficient mice are reported to lack germinal centers and plasma cells, and exhibit profound hypogammaglobulinemia.
MUM1 is found mainly in B-cell lymphoma and melanocytic lesions. Significant variation in positivity mainly due to chromosomal translocations involving MUM1 gene among T-cell lymphomas is observed. Tumours and proliferations of other than lymphocytic and melanocytic lineages are negative. + B-cell lymphoma: multiple myeloma, primary effusion lymphoma, immunoblastic lymphoma, plasmablastic lymphoma, Burkitt-like variant of diffuse large B-cell (DLBCL)(90%) and primary CNS lymphoma (90%), T-cell lymphoma: all cases of adult T-cell leukemia/lymphoma (ATLL), anaplastic large cell lymphoma (ALCL) of both ALK positive and negative types (80-95%) as well as cutaneous- ALCL (95%) Hodgkin lymphoma: 90-100% cases of classic type. Melanocytic tumours: both benign and malignant are positive in >90% with somewhat lower frequency in metastatic lesions (85%). +/- B-cell lymphoma: follicular lymphoma grade III (80%), primary mediastinal large B-cell lymphoma (75%), diffuse large B-cell lymphoma (DLBCL) (40-70%), EBV positive DLBCL of elderly, DLBCL associated with chronic inflammation, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, lymphoplasmacytic lymphoma (50%), and 50-60% of marginal zone lymphomas. T-cell lymphoma: peripheral T-cell type (30-70%). Post-transplant lymphoproliferative disorders (70%). -/+ B-cell lymphoma: 40% of small lymphocytic lymphomas (the expression is found mainly in proliferation centers); mantle cell lymphoma (>30%); lymphoblastic lymphoma (30%) and Burkitt lymphoma (10-40%). T-cell lymphoma: mycosis fungoides (40%) Hodgkin lymphoma: Varying proportion (30-70%) of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) show weak staining of L&H cells but T-lymphocytes surrounding L&H cells usually stain positive. B-cell lymphoma: low grade (I/II) of follicular lymphoma (10%), primary cutaneous DLBCL, leg type. Desmoplastic melanoma shows low frequency of positivity (15%) - T-cell lymphoma: angioimmunoblastic, hepatosplenic, subcutaneous panniculitis-like, enteropathy type and NK/T-cell lymphomas are reported negative.
MUM1 is useful in a panel with other markers for subclassification of malignant lymphomas and identification of plasma cell differentiation. Particularly MUM1 may be useful for the identification of plasma cell differentiation when morphologic evidence is lacking and Ig light chains are difficult to interpret. In contrast to CD138, MUM1 is not expresses in epithelial cells and tumours. Presence of MUM1 reactivity in DLBCL (>30% tumour cells) indicates non-germinal cell phenotype with less favorable prognosis (particularly pediatric cases), however some studies suggest that combination with other markers (e.g. FOXP1) may show better correlation with prognosis. MUM1 also dichotomizes follicular lymphomas as only the grade III (Ki67 high phenotype) is MUM1+. It should be kept in mind that MUM1 reactivity in B-lymphocytes before the plasma cell stage makes it less specific marker of plasma cells than a combination of CD138 and immunoglobulin staining. A MUM1+/S-100+/CD45-/Ig- immunoprofile indicates melanocytic differentiation in tumours. Positive staining of infiltrating lymphocytes, plasma cells and T-lymphocytes in solid tumours can be sometimes confusing. MUM1 seems also to be a promising target for the treatment of some of the MUM1 positive neoplasms.
Tonsil is recommendable as positive tissue control, where the late stage germinal centre B-cells must display a moderate to strong distinct nuclear staining. Plasma cells are strongly stained and a weak cytoplasmic staining should be accepted. By highly sensitive protocols, weak nuclear staining may be seen in a fraction of B-cells located in the mantle zone.
Colon is recommended as negative tissue control. Epithelia cells and smooth muscle cells (lamina muscularis propria) should be negative and only plasma cells located to mucosa (lamina propria) should display a strong nuclear reaction.
1. Gaidano G, Carbone A. MUM1: A step ahead toward the understanding of lymphoma histogenesis. Leukemia. 2000; 14: 563–566. 2. Grossman A, Mittrücker HW, Nicholl J, Suzuki A , Chung S, Antonio L, Suggs S, Sutherland GR, Siderovski DP, Mak TW. Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25. Genomics. 1996; 37(2):229-33. 3. Gualco G, Weiss LM, Bacchi CE. MUM1/IFR4. A Review. Appl Immunohistochem. Mol.Morphol. 2010; 4: 301-310. 4. Harada H, Taniguchi T, Tanaka N. The role of interferon regulatory factors in the interferon system and cell growth control. Biochimie. 1998; 8-9: 641-65. 5. Haarer CF, Roberts RA, Frutiger YM, Grogan TM, Rimsza LM. Immunohistochemical classification of de novo, transformed, and relapsed diffuse large B-cell lymphoma into germinal center B-cell and nongerminal center B-cell subtypes correlates with gene expression profile and patient survival. Arch Pathol Lab Med. 2006; 130: 1819-24. 6. Natkunam Y, Warnke RA, Montgomery K, Falini B, van de Rijn M. Analysis of MUM1/IRF4 Protein Expression Using Tissue Microarrays and Immunohistochemistry. Mod Pathol 2001; 14: 686–694 7. Naresh K. MUM1 expression dichotomizes follicular lymphoma into predominantly MUM1-negative low-grade and MUM1-positive high-grade subtypes. Haematologica 2007; 92: 267-268 8. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppä S. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol. 2009; 22: 1094-101. 9. Shaffer AL, Emre TNC, Romesser PB, Staudt LM. IRF4: Immunity. Malignancy! Therapy? Clin Cancer Res. 2009; 15: 2954–2961. 10. Sundram U, Harvell JD,. Rouse RV, Natkunam Y. Expression of the B-Cell Proliferation Marker MUM1 by Melanocytic Lesions and Comparison with S100, gp100 (HMB45), and MelanA. Mod Pathol 2003; 16: 802–810.