Virally Induced Cellular MicroRNA miR-155 Plays a Key Role in B-Cell Immortalization by Epstein-Barr Virus

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Blank Journal of Virology, November 2010, p. 11670-11678, Vol. 84, No. 22

0022-538X/10/$012.00+0 doi:10.1128/JVI.01248-10

Virally Induced Cellular MicroRNA miR-155 Plays a Key Role in B-Cell

Immortalization by Epstein-Barr Virus

D. Linnstaedt, Eva Gottwein, L. Skalsky, Micah A. Luftig, and

R. Cullen*

Department of Molecular Genetics and Microbiology and Center for Virology, Duke

University Medical Center, Durham, North Carolina 27710

Received 10 June 2010/ Accepted 31 August 2010

Infection of resting primary human B cells by Epstein-Barr virus (EBV) results

in their transformation into indefinitely proliferating lymphoblastoid cell

lines (LCLs). LCL formation serves as a model for lymphomagenesis, and LCLs are

phenotypically similar to EBV-positive diffuse large B-cell lymphomas (DLBCLs),

which represent a common AIDS-associated malignancy. B-cell infection by EBV

induces the expression of several cellular microRNAs (miRNAs), most notably

miR-155, which is overexpressed in many tumors and can induce B-cell lymphomas

when overexpressed in animals. Here, we demonstrate that miR-155 is the most

highly expressed miRNA in LCLs and that the selective inhibition of miR-155

function specifically inhibits the growth of both LCLs and the DLBCL cell line

IBL-1. Cells lacking miR-155 are inefficient in progressing through S phase and

spontaneously undergo apoptosis. In contrast, three other B-cell lymphoma lines,

including two EBV-positive Burkitt's lymphoma cell lines, grew normally in the

absence of miR-155 function. These data identify the induction of cellular

miR-155 expression by EBV as critical for the growth of both

laboratory-generated LCLs and naturally occurring DLBCLs and suggest that

targeted inhibition of miR-155 function could represent a novel approach to the

treatment of DLBCL in vivo.

* Corresponding author. Mailing address: Department of Molecular Genetics and

Microbiology, Box 3025, Durham, NC 27710. Phone: (919) 684-3369. Fax: (919)

681-8979. E-mail: bryan.cullen@...