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IRF4

MIM.601900 HGNC:6119 6p25-p23

Wednesday 28 October 2009

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Expression in normal cells and functions

Transcriptional factor (MUM1/IRF4, MUltiple Myeloma 1 / Interferon Regulatory Factor 4 protein) is expressed in final step of intra-germinal center B cell differentiation and in post-germinal center (late centrocyte) B cells (Blood 2000;95:2084, Appl Immunohistochem Mol Morphol 2010;18:301).

Antigen stimulated B cells with the capacity to differentiate toward plasma cells express MUM1/IRF4.

Expression in B cells (some) and plasma cells.

MUM1/IRF4 has critical role in lymphoid development and in regulating immune response. (Proc Natl Acad Sci USA 2012;109:8664)

Expression of MUM1/IRF4 is usually mutually exclusive with BCL6 in nonneoplastic tissue:
- germinal center cells are MUM1- BCL6+ CD10+
- post-germinal (non-germinal center) cells are MUM1+ BCL6- CD10-;
- Mantle cells are MUM1- BCL6- CD10-.

Expression in tumors

- Infectious mononucleosis (atypical lymphoid infiltrate with numerous MUM1+ CD10- BCL6- immunoblasts, Mod Pathol 2012;25:1149)
- B-ALL and Burkitt lymphoma (occasionally, Am J Clin Pathol 2010;133:41)
- Diffuse large B cell lymphoma (50%, Arch Pathol Lab Med 2010;134:759)
- Extranodal NK/T-cell lymphoma, nasal type (variable, Am J Surg Pathol 2012;36:481)
- Hodgkin lymphoma (classical)
- intravascular large B cell lymphoma (95%, Arch Pathol Lab Med 2012;136:333)
- ALK+ large B cell lymphoma
- Mantle cell lymphoma (35%, Appl Immunohistochem Mol Morphol 2010;18:103)
- Primary mediastinal large cell lymphoma (45%, Leuk Lymphoma 2011;52:1495)
- Post transplant lymphoproliferative disorders (EBV+); age related EBV-associated B-cell lymphoproliferative disorders
- Primary CNS lymphoma (84%, Clin Cancer Res 2006;12:1152)
- Pyothorax associated lymphoma
- Melanocytic tumors

Diagnostic use

- Nuclear stain

- MUM1 helps divide diffuse large B cell lymphomas into:

  • germinal center phenotype (MUM1-)
  • non-germinal center phenotype (post-germinal center or activated B-like, MUM1+) phenotypes;
  • germinal center phenotypes have superior outcomes (Am J Surg Pathol 2009;33:1815)

As part of panel, MUM1 may help differentiate nodular lymphocyte predominant Hodgkin lymphoma (MUM1/IRF4 negative) from classical Hodgkin lymphoma (positive, Rom J Morphol Embryol 2011;52:69)

MUM1 also helps to differentiate double-hit lymphomas (MUM1+ in 45%) from Burkitt and diffuse large B cell lymphoma (DLBCL) if they have a MUM1- germinal center phenotype (Am J Surg Pathol 2010;34:327).

Expression in tumors

- MUM1 expression in 35% of mantle cell lymphoma (MCL)

  • Mantle cell lymphoma (MCL) characteristically express CD20, CD5, and cyclin-D1, carries the translocation t(11;14) (q13;q32) and typically has no expression of germinal center cell markers.
  • So-called aberrant phenotypes such as CD5 negative and cyclin-D1-negative MCL have been described.
  • Also few cases with CD10 and/or BCL-6 protein expression have been reported.

FISH IRF4 rearrangements

IRF4 (interferon regulatory factor-4) translocations have been observed in cutaneous anaplastic large cell lymphomas.

FISH for IRF4 favors cutaneous anaplastic large cell lymphoma versus other cutaneous T cell lymphoproliferative disorders (Mod Pathol 2011;24:596)

There is a clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma.

Like all FISH studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.

- FISH detection of MUM1 / IRF4 translocation (DUSP22-IRF4) favors cutaneous anaplastic large cell lymphoma (Mod Pathol 2011;24:596)
- FISH detection of IG/IRF4 fusion detects lymphomas associated with younger patient age and favorable outcome (Blood 2011;118:139)
- t(6;14)(p25;q32), causing MUM1/IRF4-IgH, present in 20% of myeloma (Leukemia 1999;13:1812)

References

- Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies. Wada DA, Law ME, Hsi ED, Dicaudo DJ, Ma L, Lim MS, Souza AD, Comfere NI, Weenig RH, Macon WR, Erickson LA, Ozsan N, Ansell SM, Dogan A, Feldman AL. Mod Pathol. 2010 Dec 17. PMID: #21169992# [Free]

- BCL6, MUM1, and CD10 Expression in Mantle Cell Lymphoma. Gualco G, Weiss LM, Harrington WJ Jr, Bacchi CE. Appl Immunohistochem Mol Morphol. 2009 Oct 12. PMID: #19826251#