Tumor Suppressor Gene Blocks Formation of Diffuse Large B-Cell Lymphomas

Cancer researchers have identified a molecular pathway that helps to explain how the oncogene BCL6 acts to generate diffuse large B-cell lymphoma (DLBCL) and which may present opportunities for the development of specific chemotherapeutic agents to prevent or treat the disease.

BCL6 causes the majority of diffuse large B-cell lymphomas, the most common form of non-Hodgkin lymphoma. Depletion or blockade of BCL6 potently kills lymphoma cells in tissue culture, and BCL6 is thus a critical therapeutic target. Like many oncogenes and tumor suppressors, BCL6 is a transcription factor.

Investigators at New York University (NY, USA) worked with a transgenic mice model in which the animals constitutively expressed BCL6 in B-cells and developed DLBCLs similar to the human disease. They reported in the November 23, 2011, online edition of the journal Nature that BCL6 was targeted for ubiquitylation and proteasomal degradation through ubiquitin ligase-enzyme activity orchestrated by the SKP1–CUL1–F-box protein (SCF) complex that contains the orphan F-box protein FBXO11.

The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Tumor-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation, but reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death.

“We have discovered that the protein FBXO11 is a novel tumor suppressor in B-cells,” said senior author Dr. Michele Pagano, professor of oncology and pathology at New York University. “Our new research findings show deletion or mutation of the FBXO11 gene in B-cells may lead to the formation of diffuse large B-cell lymphoma.”

“These findings reveal the molecular mechanism behind the overexpression of BCL6 in B-cell lymphomas,” said Dr. Pagano. “Mutations and deletions of FBXO11 in B-cells contribute to lymphomagenesis. As lymphoma cells are addicted to BCL6 expression, FBXO11-mediated regulation of BCL6 is a new potential therapeutic strategy for the future treatment of lymphoma.”

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