ETS1 phosphorylation at threonine 38 is associated with the cell of origin of diffuse large B cell lymphoma and sustains the growth of tumour cells.
11q24.3 gain
ETS1 Thr38 phosphorylation
MEK/ERK axis
diffuse large B-cell lymphoma (DLBCL)
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
revised:
19
07
2023
received:
12
12
2022
accepted:
24
07
2023
pubmed:
16
8
2023
medline:
16
8
2023
entrez:
16
8
2023
Statut:
ppublish
Résumé
The transcriptional factor ETS1 is upregulated in 25% of diffuse large B cell lymphoma (DLBCL). Here, we studied the role of ETS1 phosphorylation at threonine 38, a marker for ETS1 activation, in DLBCL cellular models and clinical specimens. p-ETS1 was detected in activated B cell-like DLBCL (ABC), not in germinal centre B-cell-like DLBCL (GCB) cell lines and, accordingly, it was more common in ABC than GCB DLBCL diagnostic biopsies. MEK inhibition decreased both baseline and IgM stimulation-induced p-ETS1 levels. Genetic inhibition of phosphorylation of ETS1 at threonine 38 affected the growth and the BCR-mediated transcriptome program in DLBCL cell lines. Our data demonstrate that ETS1 phosphorylation at threonine 38 is important for the growth of DLBCL cells and its pharmacological inhibition could benefit lymphoma patients.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
244-254Subventions
Organisme : Rotary Foundation
ID : GG1639200
Organisme : Rotary Foundation
ID : GG1756935
Organisme : Swiss Cancer Research Foundation
ID : KLS-3580-02-2015
Informations de copyright
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-1947.
Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-690.
Wright GW, Huang DW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568. e514.
Bonetti P, Testoni M, Scandurra M, Ponzoni M, Piva R, Mensah AA, et al. Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood. 2013;122(13):2233-2241.
Priebe V, Sartori G, Napoli S, Chung EYL, Cascione L, Kwee I, et al. Role of ETS1 in the transcriptional network of diffuse large B cell lymphoma of the activated B cell-like type. Cancers (Basel). 2020;12(7):1912.
Sartori G, Napoli S, Cascione L, Chung EYL, Priebe V, Arribas AJ, et al. ASB2 is a direct target of FLI1 that sustains NF-kappaB pathway activation in germinal center-derived diffuse large B-cell lymphoma. J Exp Clin Cancer Res. 2021;40(1):357.
Seidel JJ, Graves BJ. An ERK2 docking site in the pointed domain distinguishes a subset of ETS transcription factors. Genes Dev. 2002;16(1):127-137.
Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, et al. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol. 1996;16(2):538-547.
Foulds CE, Nelson ML, Blaszczak AG, Graves BJ. Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. Mol Cell Biol. 2004;24(24):10954-10964.
Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, et al. Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP. Proc Natl Acad Sci U S A. 2010;107(22):10026-10031.
Xu-Monette ZY, Wu L, Visco C, Tai YC, Tzankov A, Liu WM, et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2012;120(19):3986-3996.
Ennishi D, Mottok A, Ben-Neriah S, Shulha HP, Farinha P, Chan FC, et al. Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. Blood. 2017;129(20):2760-2770.
Gaudio E, Tarantelli C, Spriano F, Guidetti F, Sartori G, Bordone R, et al. Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models. Haematologica. 2020;105(11):2584-2591.
Olsson MH, Sondergaard CR, Rostkowski M, Jensen JH. PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput. 2011;7(2):525-537.
Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, et al. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput. 2016;12(1):281-296.
Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein LM. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79:926-935.
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33-38.
Andrews S. FastQC a quality control tool for high throughput sequence data; 2014.
Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res. 2012;22(9):1760-1774.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21.
Anders S, Pyl PT, Huber W. HTSeq-a python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166-169.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550.
Shaffer AL, Wright G, Yang L, Powell J, Ngo V, Lamy L, et al. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol Rev. 2006;210:67-85.
Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191-w198.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139-140.
Culhane AC, Thioulouse J, Perrière G, Higgins DG. MADE4: an R package for multivariate analysis of gene expression data. Bioinformatics. 2005;21(11):2789-2790.
Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, Li Y, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26(9):2103-2113.
Shaffer AL, Emre NC, Romesser PB, Staudt LM. IRF4: immunity. Malignancy! Therapy? Clin Cancer Res. 2009;15(9):2954-2961.
Blenk S, Engelmann J, Weniger M, Schultz J, Dittrich M, Rosenwald A, et al. Germinal center B cell-like (GCB) and activated B cell-like (ABC) type of diffuse large B cell lymphoma (DLBCL): analysis of molecular predictors, signatures, cell cycle state and patient survival. Cancer Inform. 2007;3:399-420.
Plotnik JP, Budka JA, Ferris MW, Hollenhorst PC. ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. Nucleic Acids Res. 2014;42(19):11928-11940.
Holmes AB, Corinaldesi C, Shen Q, Kumar R, Compagno N, Wang Z, et al. Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome. J Exp Med. 2020;217(10):e20200483.
Young RM, Phelan JD, Wilson WH, Staudt LM. Pathogenic B-cell receptor signaling in lymphoid malignancies: new insights to improve treatment. Immunol Rev. 2019;291(1):190-213.
Pedrosa L, Fernández-Miranda I, Pérez-Callejo D, Quero C, Rodríguez M, Martín-Acosta P, et al. Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma. Sci Rep. 2021;11(1):1886.
Erman B, Sen R. Context dependent transactivation domains activate the immunoglobulin mu heavy chain gene enhancer. EMBO J. 1996;15(17):4665-4675.
Nelsen B, Tian G, Erman B, Gregoire J, Maki R, Graves B, et al. Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. Science. 1993;261(5117):82-86.
Rao E, Dang W, Tian G, Sen R. A three-protein-DNA complex on a B cell-specific domain of the immunoglobulin mu heavy chain gene enhancer. J Biol Chem. 1997;272(10):6722-6732.
Rivera RR, Stuiver MH, Steenbergen R, Murre C. Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression. Mol Cell Biol. 1993;13(11):7163-7169.
John SA, Clements JL, Russell LM, Garrett-Sinha LA. Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J Biol Chem. 2008;283(2):951-962.
Lincoln DW 2nd, Bove K. The transcription factor Ets-1 in breast cancer. Front Biosci. 2005;10:506-511.
Dittmer J. The biology of the Ets1 proto-oncogene. Mol Cancer. 2003;2:29.
Li Y, Wu T, Peng Z, Tian X, Dai Q, Chen M, et al. ETS1 is a prognostic biomarker of triple-negative breast cancer and promotes the triple-negative breast cancer progression through the YAP signaling. Am J Cancer Res. 2022;12(11):5074-5084.
Luchtel RA, Zhao Y, Aggarwal RK, Pradhan K, Maqbool SB. ETS1 is a novel transcriptional regulator of adult T-cell leukemia/lymphoma of North American descent. Blood Adv. 2022;6(20):5613-5624.
Huang L, Zhai Y, La J, Lui JW, Moore SPG, Little EC, et al. Targeting pan-ETS factors inhibits melanoma progression. Cancer Res. 2021;81(8):2071-2085.