Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas.
B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell-cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3'UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.
Lin
J
J
Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.
Lwin
T
T
Zhao
J-J
JJ
Tam
W
W
Choi
Y S
YS
Moscinski
L C
LC
Dalton
W S
WS
Sotomayor
E M
EM
Wright
K L
KL
Tao
J
J
D020413:3' Untranslated Regions / Q000502:physiology; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics*; D020566:Dendritic Cells, Follicular / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D035683:MicroRNAs / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000235:genetics*; D015854:Up-Regulation
D020413:3' Untranslated Regions; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; C487931:mirnlet7 microRNA, human; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1