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

Publication ,  Journal Article
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 ...
Published in: Haematologica
November 1, 2021

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.

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Published In

Haematologica

DOI

EISSN

1592-8721

Publication Date

November 1, 2021

Volume

106

Issue

11

Start / End Page

2927 / 2939

Location

Italy

Related Subject Headings

  • Transducin
  • Prognosis
  • Neoplasm Recurrence, Local
  • Lymphoma, Large B-Cell, Diffuse
  • Immunology
  • Humans
  • Gene Expression Profiling
  • Carcinogenesis
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Youssef, Y., Karkhanis, V., Chan, W. K., Jeney, F., Canella, A., Zhang, X., … Alinari, L. (2021). Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma. Haematologica, 106(11), 2927–2939. https://doi.org/10.3324/haematol.2020.268235
Youssef, Youssef, Vrajesh Karkhanis, Wing Keung Chan, Frankie Jeney, Alessandro Canella, Xiaoli Zhang, Shelby Sloan, et al. “Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.Haematologica 106, no. 11 (November 1, 2021): 2927–39. https://doi.org/10.3324/haematol.2020.268235.
Youssef Y, Karkhanis V, Chan WK, Jeney F, Canella A, Zhang X, et al. Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma. Haematologica. 2021 Nov 1;106(11):2927–39.
Youssef, Youssef, et al. “Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.Haematologica, vol. 106, no. 11, Nov. 2021, pp. 2927–39. Pubmed, doi:10.3324/haematol.2020.268235.
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. Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma. Haematologica. 2021 Nov 1;106(11):2927–2939.

Published In

Haematologica

DOI

EISSN

1592-8721

Publication Date

November 1, 2021

Volume

106

Issue

11

Start / End Page

2927 / 2939

Location

Italy

Related Subject Headings

  • Transducin
  • Prognosis
  • Neoplasm Recurrence, Local
  • Lymphoma, Large B-Cell, Diffuse
  • Immunology
  • Humans
  • Gene Expression Profiling
  • Carcinogenesis
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology