Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma.
Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis. Here, BMI-1 and EZH2 expression patterns are analyzed in a variety of B-cell non-Hodgkin lymphomas (B-NHLs), including small lymphocytic lymphoma, follicular lymphoma, large B-cell lymphoma, mantle-cell lymphoma, and Burkitt lymphoma. In contrast to the mutually exclusive pattern of BMI-1 and EZH2 in reactive follicles, the neoplastic cells in B-NHLs of intermediate- and high-grade malignancy showed strong coexpression of BMI-1 and EZH2. This pattern overlapped with the expression of Mib-1/Ki-67, a marker for proliferation. Neoplastic cells in B-NHL of low-grade malignancy were either BMI-1(low)/EZH2(+) (neoplastic centroblasts) or BMI-1(low)EZH2(-) (neoplastic centrocytes). These observations show that low-, intermediate-, and high grade B-NHLs are associated with increased coexpression of the BMI-1 and EZH2 PcG proteins, whose normal expression pattern is mutually exclusive. This expression pattern is probably caused by a failure to down-regulate BMI-1 in dividing neoplastic cells, because BMI-1 expression is absent from normal dividing B cells. These observations are in agreement with findings in studies of Bmi-1 transgenic mice. The extent of BMI-1/EZH2 coexpression correlated with clinical grade and the presence of Mib-1/Ki-67 expression, suggesting that the irregular expression of BMI-1 and EZH2 is an early event in the formation of B-NHL. This points to a role for abnormal PcG expression in human lymphomagenesis. (Blood. 2001;97:3896-3901)
van Kemenade
F J
FJ
Department of Pathology, VU University Hospital, Rm PA-001, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. f.vkemenade@azvu.nl
Raaphorst
F M
FM
Blokzijl
T
T
Fieret
E
E
Hamer
K M
KM
Satijn
D P
DP
Otte
A P
AP
Meijer
C J
CJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002648:Child; D018450:Disease Progression; D029721:Drosophila Proteins; D005629:Frozen Sections; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000737:chemistry* / Q000209:etiology* / Q000473:pathology; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis*
D034961:Antigens, Nuclear; C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; D029721:Drosophila Proteins; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C083329:E(z) protein, Drosophila; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1