Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines.
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 p16INK4a, 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 p16INK4a is down-regulated, 27 of 52 BMI-1POS cases of HL revealed strong nuclear expression of p16INK4a. 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 p16INK4a.
Department of Pathology, Vrije Universiteit University Medical Center (VUMC), Amsterdam, The Netherlands.
Danny F
DF
Dukers
Joost C
JC
van Galen
Cindy
C
Giroth
Patty
P
Jansen
Richard G A B
RG
Sewalt
Arie P
AP
Otte
Hanneke C
HC
Kluin-Nelemans
Chris J L M
CJ
Meijer
Frank M
FM
Raaphorst
D001402:B-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008025:Ligases; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D019941:Cyclin-Dependent Kinase Inhibitor p16; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human