Differentiation stage–specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas

Blood - Tập 113 - Trang 3754-3764 - 2009
Raquel Malumbres1, Kristopher A. Sarosiek1, Elena Cubedo1, Jose W. Ruiz1, Xiaoyu Jiang1, Randy D. Gascoyne2, Robert Tibshirani3, Izidore S. Lossos1
1Department of Medicine, Division of Hematology-Oncology and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, FL
2Department of Pathology, British Columbia Cancer Agency, Vancouver, BC
3Departments of Health Research & Policy and Statistics, Stanford University, CA

Tóm tắt

Abstract 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.

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