The Notch/Hes1 Pathway Sustains NF-κB Activation Through CYLD Repression in T Cell Leukemia

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2010 Sep 14

PMID 20832754

Citations 151

Authors

Lluis Espinosa

Severine Cathelin

Teresa DAltri

Thomas Trimarchi

Alexander Statnikov

Jordi Guiu

Veronica Rodilla

Julia Ingles-Esteve

Josep Nomdedeu

Beatriz Bellosillo

Carles Besses

Omar Abdel-Wahab

Nicole Kucine

Shao-Cong Sun

Guangchan Song

Charles C Mullighan

Ross L Levine

Klaus Rajewsky

Iannis Aifantis

Anna Bigas

Affiliations

Soon will be listed here.

Abstract

It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

Citing Articles

Modes of Notch signalling in development and disease.

Bray S, Bigas A Nat Rev Mol Cell Biol. 2025; .

PMID: 40065190 DOI: 10.1038/s41580-025-00835-2.

Crumbling Pathogenesis and Biomarkers for Diabetic Peripheral Neuropathy.

Chong Z, Souayah N Biomedicines. 2025; 13(2).

PMID: 40002826 PMC: 11853266. DOI: 10.3390/biomedicines13020413.

Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice.

Gioulbasani M, Aijo T, Liu S, Montgomery S, Montgomery N, Corcoran D Commun Biol. 2024; 7(1):1606.

PMID: 39627458 PMC: 11615039. DOI: 10.1038/s42003-024-07312-0.

Mycovirus-Containing Alters Transcription Factors in Normal and Acute Lymphoblastic Leukemia Cells.

Tebbi C, Yan J, Sahakian E, Mediavilla-Varela M, Pinilla-Ibarz J, Patel S Int J Mol Sci. 2024; 25(19).

PMID: 39408690 PMC: 11476453. DOI: 10.3390/ijms251910361.

The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia.

Abdollahzadeh B, Cantale Aeo N, Giordano N, Orlando A, Basciani M, Peruzzi G Int J Mol Sci. 2024; 25(18).

PMID: 39337370 PMC: 11431874. DOI: 10.3390/ijms25189882.

References

Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K . Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood. 2009; 114(5):1046-52. PMC: 2721785. DOI: 10.1182/blood-2009-01-199604. View

Keats J, Fonseca R, Chesi M, Schop R, Baker A, Chng W . Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007; 12(2):131-44. PMC: 2083698. DOI: 10.1016/j.ccr.2007.07.003. View

Hoffmann A, Levchenko A, Scott M, Baltimore D . The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science. 2002; 298(5596):1241-5. DOI: 10.1126/science.1071914. View

Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K . NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell. 2000; 5(6):981-92. DOI: 10.1016/s1097-2765(00)80263-4. View

Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K . Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009; 459(7247):712-6. DOI: 10.1038/nature07969. View

Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F . Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med. 2006; 13(1):70-7. DOI: 10.1038/nm1524. View

Barbie D, Tamayo P, Boehm J, Kim S, Moody S, Dunn I . Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009; 462(7269):108-12. PMC: 2783335. DOI: 10.1038/nature08460. View

Karin M . Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6. DOI: 10.1038/nature04870. View

Mumm J, Schroeter E, Saxena M, Griesemer A, Tian X, Pan D . A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell. 2000; 5(2):197-206. DOI: 10.1016/s1097-2765(00)80416-5. View

10.

Reiley W, Zhang M, Jin W, Losiewicz M, Donohue K, Norbury C . Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol. 2006; 7(4):411-7. DOI: 10.1038/ni1315. View

11.

Meylan E, Dooley A, Feldser D, Shen L, Turk E, OuYang C . Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature. 2009; 462(7269):104-7. PMC: 2780341. DOI: 10.1038/nature08462. View

12.

Egan S, St-Pierre B, Leow C . Notch receptors, partners and regulators: from conserved domains to powerful functions. Curr Top Microbiol Immunol. 1997; 228:273-324. DOI: 10.1007/978-3-642-80481-6_11. View

13.

Turpin P, Rodriguez M, Thomas D, Hay R, Virelizier J, Dargemont C . Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm. J Cell Sci. 1997; 110 ( Pt 3):369-78. DOI: 10.1242/jcs.110.3.369. View

14.

Screpanti I, Bellavia D, Campese A, Frati L, Gulino A . Notch, a unifying target in T-cell acute lymphoblastic leukemia?. Trends Mol Med. 2003; 9(1):30-5. DOI: 10.1016/s1471-4914(02)00003-5. View

15.

Mandal M, Crusio K, Meng F, Liu S, Kinsella M, Clark M . Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid. Proc Natl Acad Sci U S A. 2008; 105(52):20840-5. PMC: 2634950. DOI: 10.1073/pnas.0807557106. View

16.

ONeil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C . FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007; 204(8):1813-24. PMC: 2118656. DOI: 10.1084/jem.20070876. View

17.

Li X, Gounari F, Protopopov A, Khazaie K, von Boehmer H . Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. J Exp Med. 2008; 205(12):2851-61. PMC: 2585834. DOI: 10.1084/jem.20081561. View

18.

Bignell G, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R . Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 2000; 25(2):160-5. DOI: 10.1038/76006. View

19.

Iso T, Kedes L, Hamamori Y . HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003; 194(3):237-55. DOI: 10.1002/jcp.10208. View

20.

Rodriguez M, Wright J, Thompson J, Thomas D, Baleux F, Virelizier J . Identification of lysine residues required for signal-induced ubiquitination and degradation of I kappa B-alpha in vivo. Oncogene. 1996; 12(11):2425-35. View