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

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Blood First Edition Paper, prepublished online December 1, 2008; DOI

10.1182/blood-2008-10-184077

Differentiation-stage-specific expression of microRNAs in B-lymphocytes and

diffuse large B-cell lymphomas

Raquel Malumbres, Kristopher A. Sarosiek, Elena Cubedo, W Ruiz, Xiaoyu

Jiang, Randy D Gascoyne, Tibshirani, and Izidore S Lossos*

Department of Medicine, Division of Hematology-Oncology and Molecular and

Cellular Pharmacology, University of Miami, Sylvester Comprehensive Cancer

Center, Miami, FL, United States

Department of Pathology, British Columbia Cancer Agency, Vancouver, British

Columbia, Canada

Department of Health Research and Policy, and Statistics, Stanford University,

Stanford, CA, United States

* Corresponding author; email: ilossos@... .

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 non-transformed cellular progenitor - GC centroblasts

- aberrant miRNA expression is acquired upon cell transformation. A 9 miRNAs

signature was identified that could precisely differentiate the two major

subtypes of DLBCL. Finally, expression of some of the miRNAs in this signature

is correlated with clinical outcome of uniformly treated DLBCL patients.