Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma.

Abstract

The expression of BCL6 in B-cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions, or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase that is involved in the degradation of BCL6, and it is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of patients with Burkitt lymphoma (BL). FBXO11 mutations impaired BCL6 degradation, and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of 1 or 2 copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B-cell lymphoma onset, providing experimental evidence that FBXO11 is a haploinsufficient oncosuppressor in B-cell lymphoma. In wild-type and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degraders or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL, we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches, such as BCL6 degraders and direct MYC inhibition, could be exploited as a targeted therapy for BL.

• Authors: Chiara Pighi, Taek-Chin Cheong, Mara Compagno, Enrico Patrucco, Maddalena Arigoni, Martina Olivero, Qi Wang, Cristina López, Stephan H Bernhart, Bruno M Grande, Teresa Poggio, Fernanda Langellotto, Lisa Bonello, Riccardo Dall'Olio, Sandra Martínez-Martín, Luca Molinaro, Paola Francia di Celle, Jonathan R Whitfield, Laura Soucek, Claudia Voena, Raffaele A Calogero, Ryan D Morin, Louis M Staudt, Reiner Siebert, Alberto Zamò, Roberto Chiarle
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 23 Pg. 5239-5257 (12 14 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34625792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BCL6 protein, human
• Bcl6 protein, mouse
• F-Box Proteins
• Proto-Oncogene Proteins c-bcl-6
• FBXO11 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Animals
• Burkitt Lymphoma (drug therapy, genetics)
• F-Box Proteins (genetics)
• Genes, myc
• Humans
• Lymphoma, B-Cell (genetics)
• Mice
• Mutation
• Protein-Arginine N-Methyltransferases (genetics)
• Proto-Oncogene Proteins c-bcl-6 (genetics, metabolism)