Cell Death and Disease (Mar 2024)

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

  • Zhaohua Cai,
  • Shaojin You,
  • Zhixue Liu,
  • Ping Song,
  • Fujie Zhao,
  • Junqing An,
  • Ye Ding,
  • Ben He,
  • Ming-Hui Zou

DOI
https://doi.org/10.1038/s41419-024-06597-7
Journal volume & issue
Vol. 15, no. 3
pp. 1 – 12

Abstract

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Abstract 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.