Abstract
Aberrant activation of NF-κB is the most striking oncogenic mechanism in B-cell lymphoma; however, its role in anaplastic large cell lymphomas (ALCL) has not been fully established and its activation mechanism(s) remain unclear. Using ALCL cell line models, we revealed the supporting roles for NFKB2 and the NIK pathway in some ALCL lines. To investigate the detailed activation mechanisms for this oncogenic pathway, we performed specifically designed alternative NF-κB reporter CRISPR screens followed by the RNA-seq analysis, which led us to identify STAT3 as the major mediator for NIK-dependent NF-κB activation in ALCL. Consistently, p-STAT3 level was correlated with NFKB2 nuclear accumulation in primary clinical samples. Mechanistically, we found that in NIK-positive ALK− ALCL cells, common JAK/STAT3 mutations promote transcriptional activity of STAT3 which directly regulates NFKB2 and CD30 expression. Endogenous expression of CD30 induces constitutive NF-κB activation through binding and degrading of TRAF3. In ALK+ ALCL, the CD30 pathway is blocked by the NPM–ALK oncoprotein, but STAT3 activity and resultant NFKB2 expression can still be induced by NPM–ALK, leading to minimal alternative NF-κB activation. Our data suggest combined NIK and JAK inhibitor therapy could benefit patients with NIK-positive ALK− ALCL carrying JAK/STAT3 somatic mutations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281–4.
Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S. Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene. 1994;9:1567–74.
Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. 2006;33:58–70.
Falini B, Martelli MP. Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy. Haematologica. 2009;94:897–900.
Lazzeri D, Agostini T, Bocci G, Giannotti G, Fanelli G, Naccarato AG, et al. ALK-1-negative anaplastic large cell lymphoma associated with breast implants: a new clinical entity. Clin Breast Cancer. 2011;11:283–96.
Tsuyama N, Sakamoto K, Sakata S, Dobashi A, Takeuchi K. Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. J Clin Exp Hematop. 2017;57:120–42.
Crescenzo R, Abate F, Lasorsa E, Tabbo F, Gaudiano M, Chiesa N, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27:516–32.
Chen J, Zhang Y, Petrus MN, Xiao W, Nicolae A, Raffeld M, et al. Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. Proc Natl Acad Sci USA. 2017;114:3975–80.
Weilemann A, Grau M, Erdmann T, Merkel O, Sobhiafshar U, Anagnostopoulos I, et al. Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma. Blood. 2015;125:124–32.
Boddicker RL, Kip NS, Xing X, Zeng Y, Yang ZZ, Lee JH, et al. The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-kappaB positive feedback loop in peripheral T-cell lymphoma. Blood. 2015;125:3118–27.
Atsaves V, Lekakis L, Drakos E, Leventaki V, Ghaderi M, Baltatzis GE, et al. The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma. Br J Haematol. 2014;167:514–23.
Watanabe M, Sasaki M, Itoh K, Higashihara M, Umezawa K, Kadin ME, et al. JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma. Cancer Res. 2005;65:7628–34.
Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, et al. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res. 2001;61:2194–9.
Marzec M, Kasprzycka M, Liu X, El-Salem M, Halasa K, Raghunath PN, et al. Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene. 2007;26:5606–14.
Rothwarf DM, Karin M. The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE. 1999;1999:RE1.
Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18:2195–224.
Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565–610.
Mathas S, Johrens K, Joos S, Lietz A, Hummel F, Janz M, et al. Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood. 2005;106:4287–93.
Eckerle S, Brune V, Doring C, Tiacci E, Bohle V, Sundstrom C, et al. Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma. Leukemia. 2009;23:2129–38.
Abate F, Todaro M, van der Krogt JA, Boi M, Landra I, Machiorlatti R, et al. A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation. Leukemia. 2015;29:1390–401.
Kadin ME. Ki-1/CD30+ (anaplastic) large-cell lymphoma: maturation of a clinicopathologic entity with prospects of effective therapy. J Clin Oncol. 1994;12:884–7.
Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, et al. High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood. 1996;87:4340–7.
Zhang JP, Song Z, Wang HB, Lang L, Yang YZ, Xiao W, et al. A novel model of controlling PD-L1 expression in ALK(+) anaplastic large cell lymphoma revealed by CRISPR screening. Blood. 2019;134:171–85.
Ngo VN, Davis RE, Lamy L, Yu X, Zhao H, Lenz G, et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature. 2006;441:106–10.
Ranuncolo SM, Pittaluga S, Evbuomwan MO, Jaffe ES, Lewis BA. Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood. 2012;120:3756–63.
Yang Y, Kelly P, Shaffer AL 3rd, Schmitz R, Yoo HM, Liu X, et al. Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B cell lymphoma. Cancer Cell. 2016;29:494–507.
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.
Sun SC. The noncanonical NF-kappaB pathway. Immunol Rev. 2012;246:125–40.
Horie R, Watanabe M, Ishida T, Koiwa T, Aizawa S, Itoh K, et al. The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-kappaB activation in anaplastic large cell lymphoma. Cancer Cell. 2004;5:353–64.
Otto C, Giefing M, Massow A, Vater I, Gesk S, Schlesner M, et al. Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol. 2012;157:702–8.
Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12:115–30.
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131–44.
Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N, et al. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol. 2002;168:466–74.
Ehrentraut S, Nagel S, Scherr ME, Schneider B, Quentmeier H, Geffers R, et al. t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5. PLoS ONE. 2013;8:e53767.
Staudt LM. Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol. 2010;2:a000109.
Yang Y, Staudt LM. Protein ubiquitination in lymphoid malignancies. Immunol Rev. 2015;263:240–56.
Odqvist L, Sanchez-Beato M, Montes-Moreno S, Martin-Sanchez E, Pajares R, Sanchez-Verde L, et al. NIK controls classical and alternative NF-kappaB activation and is necessary for the survival of human T-cell lymphoma cells. Clin Cancer Res. 2013;19:2319–30.
Aizawa S, Nakano H, Ishida T, Horie R, Nagai M, Ito K, et al. Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation. J Biol Chem. 1997;272:2042–5.
Duckett CS, Gedrich RW, Gilfillan MC, Thompson CB. Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2. Mol Cell Biol. 1997;17:1535–42.
Gedrich RW, Gilfillan MC, Duckett CS, Van Dongen JL, Thompson CB. CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins. J Biol Chem. 1996;271:12852–8.
Horie R, Aizawa S, Nagai M, Ito K, Higashihara M, Ishida T, et al. A novel domain in the CD30 cytoplasmic tail mediates NFkappaB activation. Int Immunol. 1998;10:203–10.
Lee SY, Lee SY, Kandala G, Liou ML, Liou HC, Choi Y. CD30/TNF receptor-associated factor interaction: NF-kappa B activation and binding specificity. Proc Natl Acad Sci USA. 1996;93:9699–703.
Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y, et al. Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene. 2002;21:2493–503.
Buchan SL, Al-Shamkhani A. Distinct motifs in the intracellular domain of human CD30 differentially activate canonical and alternative transcription factor NF-kappaB signaling. PLoS ONE. 2012;7:e45244.
Zhang B, Calado DP, Wang Z, Frohler S, Kochert K, Qian Y, et al. An oncogenic role for alternative NF-kappaB signaling in DLBCL revealed upon deregulated BCL6 expression. Cell Rep. 2015;11:715–26.
Acknowledgements
This research was supported by American Cancer Society (ASC) IRG-92-027-21 (YY), and the Medical Research Grant from the WW. SMITH Charitable Trust (YY). The study was supported in part by the Intramural Research Program of the National Cancer Institute, NIH. The authors thank the patients for their participation. We thank D. L. Wiest (FCCC) and K.S. Campbell (FCCC) for discussions and comments. We also thank Dr. Alan L. Epstein (USC Keck School of Medicine) for the TLBR1 and TLBR2 cell lines and Dr. Annarosa Del Mistro (The Veneto Institute of Oncology) for the FE-PD cell line.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Wang, H., Wei, W., Zhang, JP. et al. A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma. Leukemia 35, 1976–1989 (2021). https://doi.org/10.1038/s41375-020-01088-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-020-01088-y
This article is cited by
-
NF-κB in biology and targeted therapy: new insights and translational implications
Signal Transduction and Targeted Therapy (2024)
-
Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified
Nature Communications (2021)