IRF4 Expression without IRF4 Rearrangement Is a General Feature of Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
2010; Elsevier BV; Volume: 130; Issue: 5 Linguagem: Inglês
10.1038/jid.2009.418
ISSN1523-1747
AutoresAnne Pham‐Ledard, Martina Prochazkova‐Carlotti, B. Vergier, Tony Petrella, Florent Grange, M. Beylot‐Barry, Jean‐Philippe Merlio,
Tópico(s)CNS Lymphoma Diagnosis and Treatment
Resumofluorescence in situ hybridization interferon regulatory factor 4 multiple myeloma multiple myeloma antigen 1 primary cutaneous diffuse large B-cell lymphoma, leg type The involvement of the interferon regulatory factor 4 gene (IRF4), also known as multiple myeloma antigen 1 (MUM1), in balanced rearrangement or translocation has been recently observed in a subset of cutaneous T-cell lymphomas (CTCLs), such as cutaneous anaplastic large-cell lymphoma (C-ALCL) and transformed mycosis fungoides (Feldman et al., 2009Feldman A.L. Law M. Remstein E.D. et al.Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.Leukemia. 2009; 23: 574-580Crossref PubMed Scopus (156) Google Scholar; Pham-Ledard et al., 2009Pham-Ledard A. Prochazkova-Carlotti M. Laharanne E. et al.IRF4 gene rearrangements define a subgroup of CD30+ cutaneous T cell lymphoma: a study of 54 cases.J Invest Dermatol. 2009Google Scholar). IRF4 expression reaches a high level in differentiated plasma cells and is also detectable by immunostaining in some activated T cells and melanocytes, with the latter providing internal positive controls on skin sections (Falini et al., 2000Falini B. Fizzotti M. Pucciarini A. et al.A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells.Blood. 2000; 95: 2084-2092PubMed Google Scholar; Lu, 2008Lu R. Interferon regulatory factor 4 and 8 in B-cell development.Trends Immunol. 2008; 29: 487-492Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Despite such a restricted immunostaining pattern, IRF4 is an essential regulator at multiple steps of B-cell differentiation, such as pre-B-cell differentiation, germinal center formation, immunoglobulin class switch recombination, and terminal differentiation of B cells to plasma cells, as shown in IRF4-deficient mice (reviewed in Shaffer et al., 2009Shaffer A.L. Emre N.C.T. Romesser P.B. et al.IRF4: immunity. Malignancy! Therapy?.Clin Cancer Res. 2009; 15: 2954-2961Crossref PubMed Scopus (128) Google Scholar). IRF4 is also essential for T-helper (Th) cell differentiation and is required for either Th2 or Th17 cell development (Brustle et al., 2007Brustle A. Heink S. Huber M. et al.The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4.Nat Immunol. 2007; 8: 958-966Crossref PubMed Scopus (512) Google Scholar; Zheng et al., 2009Zheng Y. Chaudhry A. Kas A. et al.Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.Nature. 2009; 458: 351-356Crossref PubMed Scopus (658) Google Scholar). An oncogenic role of IRF4 has first been supported by the identification of IRF4 involvement in the t(6;14)(p25;q32) translocation in some cases of multiple myeloma (MM) (Iida et al., 1997Iida S. Rao P.H. Butler M. et al.Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma.Nat Genet. 1997; 17: 226-230Crossref PubMed Scopus (291) Google Scholar). In t(6;14)(p25;q32), IRF4 is juxtaposed with the immunoglobulin heavy-chain gene locus leading to IRF4 deregulated expression (Iida et al., 1997Iida S. Rao P.H. Butler M. et al.Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma.Nat Genet. 1997; 17: 226-230Crossref PubMed Scopus (291) Google Scholar; Yoshida et al., 1999Yoshida S. Nakazawa N. Iida S. et al.Detection of MUM1/IRF4-IgH fusion in multiple myeloma.Leukemia. 1999; 13: 1812-1816Crossref PubMed Scopus (53) Google Scholar; Shaffer et al., 2008Shaffer A.L. Emre N.C. Lamy L. et al.IRF4 addiction in multiple myeloma.Nature. 2008; 454: 226-231Crossref PubMed Scopus (456) Google Scholar). Alternatively, IRF4 rearrangements in peripheral T-cell lymphoma do not commonly involve either the TCRB or the TCRA gene locus, as shown in eight C-ALCL and two systemic T-cell lymphomas (Feldman et al., 2009Feldman A.L. Law M. Remstein E.D. et al.Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.Leukemia. 2009; 23: 574-580Crossref PubMed Scopus (156) Google Scholar). Among primary cutaneous B-cell lymphomas, primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, leg type) is an original entity with poor prognosis that was first reported in 1996 and that mostly affects the leg(s) in elderly but may also arise at other sites in approximately 10% of cases (Vermeer et al., 1996Vermeer M. Geelen F. van Haselen C. et al.Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous large B-cell lymphoma with an intermediate prognosis.Arch Dermatol. 1996; 1996: 1304-1308Crossref Google Scholar; Willemze et al., 2005Willemze R. Jaffe E.S. Burg G. et al.WHO-EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3026) Google Scholar; Meijer et al., 2008Meijer C.L.J.M. Vergier B. Duncan L.M. et al.Primary Cutaneous DLBCL, Leg Type vol. 1.4th edn. International Agency for Research on Cancer, Lyon2008: 242Google Scholar). PCLBCL, leg type, differs from primary cutaneous follicle center lymphoma by the presence of confluent sheets of centroblasts and immunoblasts, many with a peculiar round cell morphology, which strongly express B-cell CLL/lymphoma 2 (BCL2), IRF4, and forkhead box P1 (FOXP1) (Willemze et al., 2005Willemze R. Jaffe E.S. Burg G. et al.WHO-EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3026) Google Scholar; Meijer et al., 2008Meijer C.L.J.M. Vergier B. Duncan L.M. et al.Primary Cutaneous DLBCL, Leg Type vol. 1.4th edn. International Agency for Research on Cancer, Lyon2008: 242Google Scholar). Interestingly, round cell morphology, strong BCL2 expression (>50% of cells), IRF4 expression (>30% of cells), or FOXP1 expression have been used to differentiate PCLBCL, leg type, from primary cutaneous follicle center lymphoma with a diffuse pattern, although 10% of the latter may express BCL2, IRF4, or less frequently FOXP1 (Kodama et al., 2005Kodama K. Massone C. Chott A. et al.Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.Blood. 2005; 106: 2491-2497Crossref PubMed Scopus (178) Google Scholar; Senff et al., 2007Senff N.J. Hoefnagel J.J. Jansen P.M. et al.Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.J Clin Oncol. 2007; 25: 1581-1587Crossref PubMed Scopus (205) Google Scholar). Strong BCL2 expression has been found in 85–100% of PCLBCL, leg type, whereas IRF4 expression was found in 68–90% of cases that may also depend on differences in fixation and antigen retrieval procedures or positivity threshold between series (Kodama et al., 2005Kodama K. Massone C. Chott A. et al.Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.Blood. 2005; 106: 2491-2497Crossref PubMed Scopus (178) Google Scholar; Grange et al., 2007Grange F. Beylot-Barry M. Courville P. et al.Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.Arch Dermatol. 2007; 143: 1144-1150Crossref PubMed Scopus (186) Google Scholar; Senff et al., 2007Senff N.J. Hoefnagel J.J. Jansen P.M. et al.Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.J Clin Oncol. 2007; 25: 1581-1587Crossref PubMed Scopus (205) Google Scholar). With some differences between series, each of these histological criteria has been reported as an independent adverse prognostic factor together with clinical parameters such as location on the leg or multiple skin lesions (Kodama et al., 2005Kodama K. Massone C. Chott A. et al.Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.Blood. 2005; 106: 2491-2497Crossref PubMed Scopus (178) Google Scholar; Grange et al., 2007Grange F. Beylot-Barry M. Courville P. et al.Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.Arch Dermatol. 2007; 143: 1144-1150Crossref PubMed Scopus (186) Google Scholar; Senff et al., 2007Senff N.J. Hoefnagel J.J. Jansen P.M. et al.Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.J Clin Oncol. 2007; 25: 1581-1587Crossref PubMed Scopus (205) Google Scholar). Conversely, IRF4 expression is a rare finding in other primary cutaneous B-cell lymphomas (Kodama et al., 2005Kodama K. Massone C. Chott A. et al.Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.Blood. 2005; 106: 2491-2497Crossref PubMed Scopus (178) Google Scholar; Willemze et al., 2005Willemze R. Jaffe E.S. Burg G. et al.WHO-EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3026) Google Scholar; Senff et al., 2007Senff N.J. Hoefnagel J.J. Jansen P.M. et al.Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.J Clin Oncol. 2007; 25: 1581-1587Crossref PubMed Scopus (205) Google Scholar). Owing to the oncogenic role of IRF4 translocation in MM and the detection of IRF4 rearrangements in a subset of CTCL with IRF4 expression (Pham-Ledard et al., 2009Pham-Ledard A. Prochazkova-Carlotti M. Laharanne E. et al.IRF4 gene rearrangements define a subgroup of CD30+ cutaneous T cell lymphoma: a study of 54 cases.J Invest Dermatol. 2009Google Scholar), we decided to analyze IRF4 expression and rearrangements in 29 cases of PCLBCL, leg type. Inclusion criteria were a complete clinical staging and follow-up to exclude lymphoma with secondary skin involvement. Formalin-fixed paraffin-embedded sections were used for immunostaining with an anti-MUM-1 antibody and for fluorescence in situ hybridization (FISH) analysis of IRF4 status with break-apart probes, as reported recently (Pham-Ledard et al., 2009Pham-Ledard A. Prochazkova-Carlotti M. Laharanne E. et al.IRF4 gene rearrangements define a subgroup of CD30+ cutaneous T cell lymphoma: a study of 54 cases.J Invest Dermatol. 2009Google Scholar). The 29 patients (mean age 82 years) had a male:female ratio of 10:19 and presented typical lesions of PCLBCL, leg type, located on the leg (n=21), upper limb (n=4), trunk (n=1), or head and neck (n=3) (see Supplementary Table S1 online). Immunostaining was scored positive in 25 out of 29 analyzed cases (86%) with >50% of tumor cells expressing IRF4 (Figure 1a,c). It was scored negative in 4 out of 29 cases (14%) with <30% positive tumor cells. BCL2 immunostaining was scored positive in 26 out of 29 cases (90%) and negative in 3 out of 29 cases (10%) with no overlap with negative IRF4 immunostaining. No case showed a break-apart or split signal. A normal FISH pattern with two fusion signals was observed in 26 out of 29 cases (90%; Figure 1b). In two cases, one extra copy of IRF4 locus with three fusion signals was observed in 64 and 75% of tumor cells, respectively (Figure 1d). A single case showed a deletion of one IRF4 allele in 67% of tumor cells (Figure 1f), although this case showed a strong IRF4 immunoreactivity (Figure 1e). Download .pdf (.01 MB) Help with pdf files Supplementary Table S1 Our study clearly shows that the typical IRF4 expression by PCLBCL, leg type, is not associated with IRF4 gene rearrangement or amplification. Moreover, extra copy of IRF4 allele was not associated with an increase in IRF4 immunostaining pattern, as previously reported in CTCL (Pham-Ledard et al., 2009Pham-Ledard A. Prochazkova-Carlotti M. Laharanne E. et al.IRF4 gene rearrangements define a subgroup of CD30+ cutaneous T cell lymphoma: a study of 54 cases.J Invest Dermatol. 2009Google Scholar). Alternatively, the four PCLBCL, leg type, cases with negative IRF4 immunostaining showed a normal FISH pattern and the single case with IRF4 monoallelic deletion was strongly IRF4 positive. Therefore, IRF4 expression in PCLBCL, leg type, is likely to be the result of several mechanisms, including differentiation stage, epigenetic regulation, or other oncogenes deregulation. Recent data have shown that constitutive activation of the intrinsic-mediated apoptosis pathway with concomitant downstream inhibition of this pathway may support the cellular resistance of PCLBCL, leg type, to chemotherapy (van Galen et al., 2008van Galen J.C. Hoefnagel J.J. Vermeer M.H. et al.Profiling of apoptosis genes identifies distinct types of primary cutaneous large B cell lymphoma.J Pathol. 2008; 215: 340-346Crossref PubMed Scopus (15) Google Scholar). Moreover, RNA interference with IRF4 expression is lethal in MM cell lines, irrespective of IRF4 genetic status (Shaffer et al., 2009Shaffer A.L. Emre N.C.T. Romesser P.B. et al.IRF4: immunity. Malignancy! Therapy?.Clin Cancer Res. 2009; 15: 2954-2961Crossref PubMed Scopus (128) Google Scholar). Whether PCLBCL, leg type, is addicted to the presence of IRF4 and dependent upon its functions for tumor cell survival or proliferation has to be further analyzed. The authors state no conflict of interest. This work was supported by grants from the Region Aquitaine, Ligue contre le Cancer, and Institut National contre le Cancer (INCa). We thank the following members of the French Study Group of Cutaneous Lymphoma for providing clinical information and/or a sample of their patients: Pr M Bagot and Dr J Wechsler, CHU Henri-Mondor, Créteil, France; Pr L Vaillant and Dr A de Muret, Tours, France; Dr S Dallac, CHU Dijon, Dijon, France; Dr Eve Maubec, CHU Bichat, Paris, France; Pr P Joly, Dr P Courville, CHU Rouen, Rouen, France; Dr B Balme, CHU E Herriot, Lyon, France, Dr AL Goeldel, CHU Reims, Reims, France; and Dr P Guillot, Clinique Wallerstein, Arès, France. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
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