Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas.
miRNAs are small RNA molecules binding to partially complementary sites in the 3'-UTR of target transcripts and repressing their expression. miRNAs orchestrate multiple cellular functions and play critical roles in cell differentiation and cancer development. We analyzed miRNA profiles in B-cell subsets during peripheral B-cell differentiation as well as in diffuse large B-cell lymphoma (DLBCL) cells. Our results show temporal changes in the miRNA expression during B-cell differentiation with a highly unique miRNA profile in germinal center (GC) lymphocytes. We provide experimental evidence that these changes may be physiologically relevant by demonstrating that GC-enriched hsa-miR-125b down-regulates the expression of IRF4 and PRDM1/BLIMP1, and memory B cell-enriched hsa-miR-223 down-regulates the expression of LMO2. We further demonstrate that although an important component of the biology of a malignant cell is inherited from its nontransformed cellular progenitor-GC centroblasts-aberrant miRNA expression is acquired upon cell transformation. A 9-miRNA signature was identified that could precisely differentiate the 2 major subtypes of DLBCL. Finally, expression of some of the miRNAs in this signature is correlated with clinical outcome of uniformly treated DLBCL patients.
Malumbres
Raquel
R
Department of Medicine, Division of Hematology-Oncology and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, FL 33136, USA.
Sarosiek
Kristopher A
KA
Cubedo
Elena
E
Ruiz
Jose W
JW
Jiang
Xiaoyu
X
Gascoyne
Randy D
RD
Tibshirani
Robert
R
Lossos
Izidore S
IS
D048868:Adaptor Proteins, Signal Transducing; D016175:B-Lymphocyte Subsets / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D060588:LIM Domain Proteins; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D008667:Metalloproteins / Q000096:biosynthesis; D035683:MicroRNAs / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis; D000099218:Interferon Regulatory Factor-4
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D060588:LIM Domain Proteins; D008667:Metalloproteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D000099218:Interferon Regulatory Factor-4; C085117:LMO2 protein, human; C531888:MIRN125 microRNA, human; C525067:MIR223, human; C087042:PRDM1 protein, human