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* Department of Pathology, Columbia University Medical Center, New York, NY 10032;
Institute for Cancer Genetics, Columbia University, New York, NY 10032;
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10467; and
Division of Molecular Immunology, Department of Internal Medicine, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, Erlangen, Germany
The transit of T cell-activated B cells through the germinal center (GC) is controlled by sequential activation and repression of key transcription factors, executing the pre- and post-GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary for GC formation and for its molecular activity in Pax5+PU.1+ B cells. IRF4, which is highly expressed in BCL6– GC B cells, is necessary for class switch recombination and the plasma cell differentiation at exit from the GC. In this study, we show at the single-cell level broad coexpression of IRF4 with BCL6, Pax5, IRF8, and PU.1 in pre- and post-GC B cells in human and mouse. IRF4 is down-regulated in BCL6+ human GC founder cells (IgD+CD38+), is absent in GC centroblasts, and is re-expressed in positive regulatory domain 1-positive centrocytes, which are negative for all the B cell transcription factors. Activated (CD30+) and activation-induced cytidine deaminase-positive extrafollicular blasts coexpress Pax5 and IRF4. PU.1-negative plasma cells and CD30+ blasts uniquely display the conformational epitope of IRF4 recognized by the MUM1 Ab, an epitope that is absent from any other IRF4+PU.1+ lymphoid and hemopoietic subsets. Low grade B cell lymphomas, representing the malignant counterpart of pre- and post-GC B cells, accordingly express IRF4. However, a fraction of BCL6+ diffuse large B cell lymphomas express IRF4 bearing the MUM1 epitope, indicative of a posttranscriptional modification of IRF4 not seen in the normal counterpart.
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1 Address correspondence and reprint requests to Dr. Giorgio Cattoretti at the current address: Department of Pathology, Azienda Ospedaliera San Gerardo, Via Pergolesi 33, 20052 Monza (MI), Italy. E-mail address: giocatto{at}gmail.com
2 Abbreviations used in this paper: TF, transcription factor; IRF, IFN regulatory factor; GC, germinal center; AID, activation-induced cytidine deaminase; BCL, B cell lymphoma; DLBCL, diffuse large BCL; IHC, immunohistochemistry; DAPI, 4',6'-diamidino-2-phenylindole; TMA, tissue microarray; FCM, flow cytometry; CLL, chronic lymphocytic leukemia; PRDM1, positive regulatory domain 1.
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