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(American Journal of Pathology. 2004;164:873-881.)
© 2004 American Society for Investigative Pathology

Unique Polycomb Gene Expression Pattern in Hodgkin’s Lymphoma and Hodgkin’s Lymphoma-Derived Cell Lines

Danny F. Dukers^*, Joost C. van Galen^*, Cindy Giroth^*, Patty Jansen, Richard G.A.B. Sewalt, Arie P. Otte, Hanneke C. Kluin-Nelemans, Chris J.L.M. Meijer^* and Frank M. Raaphorst^*

From the Department of Pathology,^* Vrije Universiteit University Medical Center (VUMC), Amsterdam; the Department of Pathology, Leiden University Medical Center (LUMC), Leiden; Swammerdam Institute for Life Sciences, Biocentrum Amsterdam, University of Amsterdam, Amsterdam; and the Department of Hematology, Groningen University Hospital, The Netherlands

Human Polycomb-group (PcG) genes play a crucial role in the regulation of embryonic development and regulation of the cell cycle and hematopoiesis. PcG genes encode proteins that form two distinct PcG complexes, involved in maintenance of cell identity and gene silencing patterns. We recently showed that expression of the BMI-1 and EZH2 PcG genes is separated during normal B-cell development in germinal centers, whereas Hodgkin/Reed-Sternberg (H/RS) cells co-express BMI-1 and EZH2. In the current study, we used immunohistochemistry and immunofluorescence to determine whether the binding partners of these PcG proteins are also present in H/RS cells and H/RS-derived cell lines. PcG expression profiles were analyzed in combination with expression of the cell cycle inhibitor p16^INK4a, because experimental model systems indicate that p16 is a downstream target of Bmi-1. We found that H/RS cells and HL-derived cell lines co-express all core proteins of the two known PcG complexes, including BMI-1, MEL-18, RING1, HPH1, HPC1, and -2, EED, EZH2, YY1, and the HPC2 binding partner, CtBP. Expression of HPC1 has not been found in normal mature B cells and other malignant lymphomas of B-cell origin, suggesting that the PcG expression profile of H/RS is unique. In contrast to Bmi-1 transgenic mice where p16^INK4a is down-regulated, 27 of 52 BMI-1^POS cases of HL revealed strong nuclear expression of p16^INK4a. We propose that abnormal expression of BMI-1 and its binding partners in H/RS cells contributes to development of HL. However, abnormal expression of BMI-1 in HL is not necessarily associated with down-regulation of p16^INK4a.

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