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Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma
Youssef Youssef1, Vrajesh Karkhanis1, Wing Keung Chan1
1Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH.
Haematologica
|October 15, 2020
Summary
Transducin β-like protein 1 (TBL1) is overexpressed in Diffuse large B-cell lymphoma (DLBCL), correlating with poor outcomes. Targeting TBL1 with drugs like tegavivint shows promise for treating DLBCL by promoting cancer cell death.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma, with subtypes identified by gene expression.
- Current chemo-immunotherapy cures two-thirds of patients, but refractory or relapsed cases have a poor prognosis, necessitating new therapies.
Purpose of the Study:
- To investigate the role of Transducin β-like protein 1 (TBL1) in DLBCL pathogenesis.
- To evaluate TBL1 as a potential therapeutic target in DLBCL.
Main Methods:
- Analysis of TBL1 expression in DLBCL cells and correlation with clinical outcome.
- Genetic deletion of TBL1 and pharmacological inhibition using tegavivint in DLBCL models.
- Integrated genomic, biochemical, and pharmacologic analyses to elucidate TBL1's function.
Main Results:
- DLBCL cells express abundant TBL1, and its overexpression is linked to poor clinical outcomes across molecular subtypes.
- Genetic and pharmacological targeting of TBL1 induced DLBCL cell death in vitro and in vivo.
- TBL1 was found to have a novel, β-CATENIN-independent, post-transcriptional oncogenic function in DLBCL.
Conclusions:
- TBL1 plays a significant role in DLBCL progression and is associated with adverse clinical outcomes.
- Targeting TBL1 represents a promising novel therapeutic strategy for Diffuse large B-cell lymphoma.
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