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BLIMP1 Is a Tumor Suppressor Gene Frequently Disrupted in Activated B Cell-like Diffuse Large B Cell Lymphoma

2010; Cell Press; Volume: 18; Issue: 6 Linguagem: Inglês

10.1016/j.ccr.2010.10.030

1878-3686

Jonathan Mandelbaum, Govind Bhagat, Hongyan Tang, Tongwei Mo, Manisha Brahmachary, Qiong Shen, Amy Chadburn, Klaus Rajewsky, Alexander Tarakhovsky, Laura Pasqualucci, Riccardo Dalla‐Favera,

Viral-associated cancers and disorders

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. These phenotypic subtypes segregate with largely unique genetic lesions, suggesting the involvement of different pathogenetic mechanisms. In this report we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in ∼53% of ABC-DLBCL. In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL. These results demonstrate that BLIMP1 is a bona fide tumor-suppressor gene whose loss contributes to lymphomagenesis by blocking plasma cell differentiation.