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Characteristics
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-κB 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.
Neoplasms
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.
Application
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.
Visualisation
Monoclonal mouse antibody (MUM1p) is most commonly in use but
polyclonal antibody (ICSTAT) is reported to have a similar
performance. HIER in an alkaline pH buffer seems to be most
effective.
Control tissue:
tonsil - strong nuclear staining with weaker cytoplasmic staining
should be demonstrated in a proportion of germinal center cells as
well as in plasma cells and some T-lymphocytes in interfollicular
areas.
Assessments
Run 32
2011
References
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. |
