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Molecular and Cellular Biology, July 2006, p. 5348-5359, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02351-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

BAL1 and BBAP Are Regulated by a Gamma Interferon-Responsive Bidirectional Promoter and Are Overexpressed in Diffuse Large B-Cell Lymphomas with a Prominent Inflammatory Infiltrate

Przemyslaw Juszczynski,1 Jeffery L. Kutok,2 Cheng Li,3 Joydeep Mitra,1 Ricardo C. T. Aguiar,1,{dagger} and Margaret A. Shipp1*

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts,1 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts,2 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts3

Received 8 December 2005/ Returned for modification 13 February 2006/ Accepted 28 April 2006

BAL1 is a transcription modulator that is overexpressed in chemoresistant, diffuse large B-cell lymphomas (DLBCLs). BAL1 complexes with a recently described DELTEX family member termed BBAP. Herein, we characterized BAL1 and BBAP expression in primary DLBCL subtypes defined by their comprehensive transcriptional profiles. BAL1 and BBAP were most abundant in lymphomas with a brisk host inflammatory response, designated host response (HR) tumors. Although these DLBCLs include significant numbers of tumor-infiltrating lymphocytes and interdigitating dendritic cells, BAL1 and BBAP were expressed primarily by malignant B cells, prompting speculation that the genes might be induced by host-derived inflammatory mediators such as gamma interferon (IFN-{gamma}). In fact, IFN-{gamma} induced BAL1 and BBAP expression in DLBCL cell lines; doxycycline-induced BAL1 also increased the expression of multiple IFN-stimulated genes, directly implicating BAL1 in an IFN signaling pathway. We show that BAL1 and BBAP are located on chromosome 3q21 in a head-to-head orientation and are regulated by a IFN-{gamma}-responsive bidirectional promoter. BBAP regulates the subcellular localization of BAL1 by a dynamic shuttling mechanism, highlighting the functional requirement for coordinated BBAP and BAL1 expression. IFN-{gamma}-induced BAL1/BBAP expression contributes to the molecular signature of HR DLBCLs and highlights the interplay between the inflammatory infiltrate and malignant B cells in these tumors.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3874. Fax: (617) 632-4734. E-mail: Margaret_Shipp{at}dfci.harvard.edu.

{dagger} Present address: Department of Medicine and San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio, TX 78229.

Molecular and Cellular Biology, July 2006, p. 5348-5359, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02351-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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