@article{Youssef_Karkhanis_Chan_Jeney_Canella_Zhang_Sloan_Prouty_Helmig-Mason_Tsyba_Hanel_Zheng_Zhang_Chung_Lucas_Kauffman_Larkin_Strohecker_Ozer_Lapalombella_Zhou_Xu-Monette_Young_Han_Nurmemmedov_Nuovo_Maddocks_Byrd_Baiocchi_Alinari_2020, place={Pavia, Italy}, title={Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma}, volume={106}, url={https://haematologica.org/article/view/haematol.2020.268235}, DOI={10.3324/haematol.2020.268235}, abstractNote={<p>Diffuse large B-cell lymphoma (DLBCL) is the most common non- Hodgkin 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 b-like protein 1 (TBL1) is an exchange adaptor protein encoded by the <em>TBL1X</em> gene and known to function as a master regulator of the Wnt signaling 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 <em>in vitro</em> and <em>in vivo</em>. 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.</p&gt;}, number={11}, journal={Haematologica}, author={Youssef, Youssef and Karkhanis, Vrajesh and Chan, Wing Keung and Jeney, Frankie and Canella, Alessandro and Zhang, Xiaoli and Sloan, Shelby and Prouty, Alexander and Helmig-Mason, JoBeth and Tsyba, Liudmyla and Hanel, Walter and Zheng, Xuguang and Zhang, Pu and Chung, Ji-Hyun and Lucas, David M. and Kauffman, Zachary and Larkin, Karilyn and Strohecker, Anne M. and Ozer, Hatice G. and Lapalombella, Rosa and Zhou, Hui and Xu-Monette, Zijun Y. and Young, Ken H. and Han, Ruolan and Nurmemmedov, Elmar and Nuovo, Gerard and Maddocks, Kami and Byrd, John C. and Baiocchi, Robert A. and Alinari, Lapo}, year={2020}, month={Sep.}, pages={2927-2939} }