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
TL;DR
Deleting FBW7 in specific endothelial cells causes B-cell lymphoma in mice, offering a new model for studying and treating this cancer.
Contribution
This study reveals that FBW7 deletion in VE-cadherin-positive endothelial cells leads to BCL6-driven lymphoma, establishing a novel preclinical model.
Findings
Endothelial cell-specific deletion of Fbw7 causes diffuse large B-cell lymphoma in mice.
FBW7 interacts with Bcl6 and promotes its degradation, and their expression is inversely correlated.
Pharmacological disruption of Bcl6 prevents lymphomagenesis caused by Fbw7 deletion.
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.…
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Taxonomy
TopicsAcute Myeloid Leukemia Research · Hematopoietic Stem Cell Transplantation · Zebrafish Biomedical Research Applications