Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Journal Article (Journal Article)

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin β-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signalling pathway by binding to β-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B-cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, β-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.

Full Text

Duke Authors

Cited Authors

  • Youssef, Y; Karkhanis, V; Chan, WK; Jeney, F; Canella, A; Zhang, X; Sloan, S; Prouty, A; Helmig-Mason, J; Tsyba, L; Hanel, W; Zheng, X; Zhang, P; Chung, J-H; Lucas, DM; Kauffman, Z; Larkin, K; Strohecker, AM; Ozer, HG; Lapalombella, R; Zhou, H; Xu-Monette, ZY; Young, KH; Han, R; Nurmemmedov, E; Nuovo, G; Maddocks, K; Byrd, JC; Baiocchi, RA; Alinari, L

Published Date

  • September 14, 2020

Published In

Volume / Issue

  • Online ahead of print /

PubMed ID

  • 33054136

Electronic International Standard Serial Number (EISSN)

  • 1592-8721

Digital Object Identifier (DOI)

  • 10.3324/haematol.2020.268235

Language

  • eng

Conference Location

  • Italy