Selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin-positive cells instigates diffuse large B-cell lymphoma in mice in vivo

• Published in: Cell death & disease Vol. 15; no. 3; pp. 212 - 12
• Main Authors: Cai, Zhaohua, You, Shaojin, Liu, Zhixue, Song, Ping, Zhao, Fujie, An, Junqing, Ding, Ye, He, Ben, Zou, Ming-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.03.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/51; 14/1; 14/19; 14/35; 631/337/474/2073; 631/67/70; 82/1; Animals; Antibodies; Antigens, CD; B-cell lymphoma; Bcl-6 protein; Biochemistry; Biomedical and Life Sciences; Cadherins; Cell Biology; Cell Culture; Cell differentiation; Clonal deletion; Endothelial cells; Endothelial Cells - metabolism; Endothelium; F-Box-WD Repeat-Containing Protein 7 - genetics; F-Box-WD Repeat-Containing Protein 7 - metabolism; Genetic transformation; Hematopoietic stem cells; Hemopoiesis; Immunology; Life Sciences; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Mice; Mice, Knockout; Progenitor cells; Proteasomes; Therapeutic applications; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06597-7

During the maturation of hematopoietic stem/progenitor cells (HSPCs) to fully differentiated mature B lymphocytes, developing lymphocytes may undergo malignant transformation and produce B-cell lymphomas. Emerging evidence shows that through the endothelial-hematopoietic transition, specialized endothelial cells called the hemogenic endothelium can differentiate into HSPCs. However, the contribution of genetic defects in hemogenic endothelial cells to B-cell lymphomagenesis has not yet been investigated. Here, we report that mice with endothelial cell-specific deletion of Fbw7 spontaneously developed diffuse large B-cell lymphoma (DLBCL) following Bcl6 accumulation. Using lineage tracing, we showed that B-cell lymphomas in Fbw7 knockout mice were hemogenic endothelium-derived. Mechanistically, we found that FBW7 directly interacted with Bcl6 and promoted its proteasomal degradation. FBW7 expression levels are inversely correlated with BCL6 expression. Additionally, pharmacological disruption of Bcl6 abolished Fbw7 deletion-induced B-cell lymphomagenesis. We conclude that selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin positive endothelial cells instigates diffuse large B-cell lymphoma via upregulation of BCL6 stability. In addition, the mice with endothelial cell-specific deletion of Fbw7 provide a valuable preclinical platform for in vivo development and evaluation of novel therapeutic interventions for the treatment of DLBCL.