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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2067-2074.
Prepublished online as a Blood First Edition Paper on June 1, 2007; DOI 10.1182/blood-2007-01-069575.
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Submitted January 31, 2007
Accepted May 28, 2007
BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms
Samir Parekh, Jose M Polo, Rita Shaknovich, Przemyslaw Juszczynski, Paola Lev, Stella M Ranuncolo, Yingnan Yin, Ulf Klein, Giorgio Cattoretti, Riccardo Dalla Favera, Margaret A. Shipp, and Ari Melnick*
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, United States
Institute of Cancer Genetics, Columbia University, New York, NY, United States
Department of Pathology, Universita degli Studi di Milano-Bicocca, Monza, Italy
* Corresponding author; email: amelnick{at}aecom.yu.edu.
The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCL). Constitutive expression of BCL6 mediates lymphomagenesis through aberrant proliferation, survival and differentiation blockade. Binding of BCL6 to the SMRT/N-CoR corepressors mediates the BCL6 survival effect in DLBCL. Although the basis for differentiation blockade is unknown in DLBCL, recent data suggest that BCL6 binding to the MTA3 corepressor might be involved. We report that BCL6 and MTA3 are co-expressed in normal germinal center B-cells and DLBCL. Depletion of MTA3 in DLBCL cells induced a differentiation-related BCL6 target gene (PRDM1) but not target genes involved in survival. Accordingly, MTA3 and PRDM1 expression are mutually exclusive in germinal center B-cells. We performed ChIP-on-chip mapping of the PRDM1 locus identifying a novel BCL6 binding site on intron 3 of the PRDM1 gene and show that BCL6 recruits MTA3 to this site. In DLBCL cells MTA3 depletion induced plasmacytic differentiation but did not decrease viability of DLBCL cells. However, MTA3 depletion synergized with a specific BCL6 inhibitor that blocks SMRT/N-CoR binding to decrease DLBCL viability. Taken together these results show that BCL6 regulates distinct transcriptional programs through the SMRT/N-CoR and MTA3 corepressors respectively, and provides a basis for combinatorial therapeutic targeting of BCL6.
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