Abstract
The nuclear factor κB or NF-κB transcription factor family plays a key role in several cellular functions, i.e. inflammation, apoptosis, cell survival, proliferation, angiogenesis, and innate and acquired immunity. The constitutive activation of NF-κB is typical of most malignancies and plays a major role in tumorigenesis. In this review, we describe NF-κB and its two pathways: the canonical pathway (RelA/p50) and the non-canonical pathway (RelB/p50 or RelB/p52). We then consider the role of the NF-κB subunits in the development and functional activity of B cells, T cells, macrophages and dendritic cells, which are the targets of hematological malignancies. The relevance of the two pathways is described in normal B and T cells and in hematological malignancies, acute and chronic leukemias (ALL, AML, CLL, CML), B lymphomas (DLBCLs, Hodgkin’s lymphoma), T lymphomas (ATLL, ALCL) and multiple myeloma. We describe the interaction of NF-κB with the apoptotic pathways induced by TRAIL and the transcription factor p53. Finally, we discuss therapeutic anti-tumoral approaches as mono-therapies or combination therapies aimed to block NF-κB activity and to induce apoptosis (PARAs and Nutlin-3).
Similar content being viewed by others
References
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205
Karin M, Cao Y, Greten FR, Li ZW (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2(4):301–310. doi:10.1038/nrc780
Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12(8):715–723. doi:10.1038/ni.2060
Huang DB, Vu D, Ghosh G (2005) NF-kappaB RelB forms an intertwined homodimer. Structure 13(9):1365–1373. doi:10.1016/j.str.2005.06.018
Vu D, Huang DB, Vemu A, Ghosh G (2013) A structural basis for selective dimerization by NF-kappaB RelB. J Mol Biol 425(11):1934–1945. doi:10.1016/j.jmb.2013.02.020
Derudder E, Dejardin E, Pritchard LL, Green DR, Korner M, Baud V (2003) RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100. J Biol Chem 278(26):23278–23284. doi:10.1074/jbc.M300106200
Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng PH, Keats JJ, Wang H, Vignali DA, Bergsagel PL, Karin M (2008) Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol 9(12):1364–1370. doi:10.1038/ni.1678
Sen R, Baltimore D (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47(6):921–928. doi:10.1016/0092-8674(86)90807-X
Gerondakis S, Grossmann M, Nakamura Y, Pohl T, Grumont R (1999) Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. Oncogene 18(49):6888–6895. doi:10.1038/sj.onc.1203236
Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C, Snapper CM, Bravo R (1998) Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 187(2):185–196. doi:10.1084/jem.187.2.185
Franzoso G, Carlson L, Poljak L, Shores EW, Epstein S, Leonardi A, Grinberg A, Tran T, Scharton-Kersten T, Anver M, Love P, Brown K, Siebenlist U (1998) Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med 187(2):147–159. doi:10.1084/jem.187.2.147
Weih DS, Yilmaz ZB, Weih F (2001) Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol 167(4):1909–1919
Grigoriadis G, Zhan Y, Grumont RJ, Metcalf D, Handman E, Cheers C, Gerondakis S (1996) The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations. EMBO J 15(24):7099–7107
Gerondakis S, Strasser A, Metcalf D, Grigoriadis G, Scheerlinck JY, Grumont RJ (1996) Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci USA 93(8):3405–3409. doi:10.1073/pnas.93.8.3405
Horwitz BH, Scott ML, Cherry SR, Bronson RT, Baltimore D (1997) Failure of lymphopoiesis after adoptive transfer of NF-kappaB-deficient fetal liver cells. Immunity 6(6):765–772. doi:10.1016/S1074-7613(00)80451-3
Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274(5288):782–784. doi:10.1126/science.274.5288.782
Doi TS, Takahashi T, Taguchi O, Azuma T, Obata Y (1997) NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med 185((5):953–961. doi:10.1084/jem.185.5.953
Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA (2002) Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16(2):257–270. doi:10.1016/S1074-7613(02)00272-8
Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R (1997) p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(−/−)relB(−/−) double-knockout mice. J Exp Med 185(7):1359–1370. doi:10.1084/jem.185.7.1359
Weih F, Warr G, Yang H, Bravo R (1997) Multifocal defects in immune responses in RelB-deficient mice. J Immunol 158(11):5211–5218
Caamano J, Alexander J, Craig L, Bravo R, Hunter CA (1999) The NF-kappa B family member RelB is required for innate and adaptive immunity to Toxoplasma gondii. J Immunol 163(8):4453–4461
Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R, Lo D (1995) Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373(6514):531–536. doi:10.1038/373531a0
Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80(2):331–340. doi:10.1016/0092-8674(95)90416-6
Wu L, D’Amico A, Winkel KD, Suter M, Lo D, Shortman K (1998) RelB is essential for the development of myeloid-related CD8alpha-dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 9(6):839–847. doi:10.1016/S1074-7613(00)80649-4
Grigoriadis G, Vasanthakumar A, Banerjee A, Grumont R, Overall S, Gleeson P, Shannon F, Gerondakis S (2011) c-Rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells. PLoS One 6(10):e26851. doi:10.1371/journal.pone.0026851
Grossmann M, Metcalf D, Merryfull J, Beg A, Baltimore D, Gerondakis S (1999) The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci USA 96(21):11848–11853. doi:10.1073/pnas.96.21.11848
Grossmann M, O’Reilly LA, Gugasyan R, Strasser A, Adams JM, Gerondakis S (2000) The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J 19(23):6351–6360. doi:10.1093/emboj/19.23.6351
Grumont RJ, Rourke IJ, O’Reilly LA, Strasser A, Miyake K, Sha W, Gerondakis S (1998) B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med 187(5):663–674. doi:10.1084/jem.187.5.663
Sha WC, Liou HC, Tuomanen EI, Baltimore D (1995) Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80(2):321–330. doi:10.1016/0092-8674(95)90415-8
Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11(24):3482–3496. doi:10.1101/gad.11.24.3482
Beg AA, Sha WC, Bronson RT, Baltimore D (1995) Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev 9(22):2736–2746. doi:10.1101/gad.9.22.2736
Klement JF, Rice NR, Car BD, Abbondanzo SJ, Powers GD, Bhatt PH, Chen CH, Rosen CA, Stewart CL (1996) IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Mol Cell Biol 16(5):2341–2349
Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189(11):1839–1845. doi:10.1084/jem.189.11.1839
Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL, Goeddel DV (1999) Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 10(4):421–429. doi:10.1016/S1074-7613(00)80042-4
Yamada T, Mitani T, Yorita K, Uchida D, Matsushima A, Iwamasa K, Fujita S, Matsumoto M (2000) Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase. J Immunol 165(2):804–812
Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284(5412):316–320. doi:10.1126/science.284.5412.316
Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N, Akira S (1999) Limb and skin abnormalities in mice lacking IKKalpha. Science 284(5412):313–316. doi:10.1126/science.284.5412.313
Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M (2001) Activation by IKKalpha of a second, evolutionary conserved. NF-kappa B signaling pathway. Science 293(5534):1495–1499. doi:10.1126/science.1062677
Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C, Li ZW, Karin M, Ware CF, Green DR (2002) The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17(4):525–535. doi:10.1016/S1074-7613(02)00423-5
Bonizzi G, Bebien M, Otero DC, Johnson-Vroom KE, Cao Y, Vu D, Jegga AG, Aronow BJ, Ghosh G, Rickert RC, Karin M (2004) Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J 23(21):4202–4210. doi:10.1038/sj.emboj.7600391
Gasparini C, Feldmann M (2012) NF-kappaB as a target for modulating inflammatory responses. Curr Pharm Des 18(35):5735–5745. doi:10.2174/138161212803530763
Pomerantz JL, Baltimore D (2002) Two pathways to NF-kappaB. Mol Cell 10(4):693–695. doi:10.1016/S1097-2765(02)00697-4
Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288. doi:10.1016/j.it.2004.03.008
Buchan SL, Al-Shamkhani A (2012) Distinct motifs in the intracellular domain of human CD30 differentially activate canonical and alternative transcription factor NF-kappaB signaling. PLoS One 7(9):e45244. doi:10.1371/journal.pone.0045244
Theill LE, Boyle WJ, Penninger JM (2002) RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795–823. doi:10.1146/annurev.immunol.20.100301.064753
Rauert H, Wicovsky A, Muller N, Siegmund D, Spindler V, Waschke J, Kneitz C, Wajant H (2010) Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J Biol Chem 285(10):7394–7404. doi:10.1074/jbc.M109.037341
Young RM, Staudt LM (2013) Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 12(3):229–243. doi:10.1038/nrd3937
Weil R, Israel A (2006) Deciphering the pathway from the TCR to NF-kappaB. Cell Death Differ 13(5):826–833. doi:10.1038/sj.cdd.4401856
Sun SC (2011) Non-canonical NF-kappaB signaling pathway. Cell Res 21(1):71–85. doi:10.1038/cr.2010.177
Gerondakis S, Banerjee A, Grigoriadis G, Vasanthakumar A, Gugasyan R, Sidwell T, Grumont RJ (2012) NF-kappaB subunit specificity in hemopoiesis. Immunol Rev 246(1):272–285. doi:10.1111/j.1600-065X.2011.01090.x
Bottero V, Withoff S, Verma IM (2006) NF-kappaB and the regulation of hematopoiesis. Cell Death Differ 13(5):785–797. doi:10.1038/sj.cdd.4401888
Jimi E, Phillips RJ, Rincon M, Voll R, Karasuyama H, Flavell R, Ghosh S (2005) Activation of NF-kappaB promotes the transition of large, CD43+ pre-B cells to small, CD43-pre-B cells. Int Immunol 17(6):815–825. doi:10.1093/intimm/dxh263
Derudder E, Cadera EJ, Vahl JC, Wang J, Fox CJ, Zha S, van Loo G, Pasparakis M, Schlissel MS, Schmidt-Supprian M, Rajewsky K (2009) Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. Nat Immunol 10(6):647–654. doi:10.1038/ni.1732
Siebenlist U, Brown K, Claudio E (2005) Control of lymphocyte development by nuclear factor-kappaB. Nat Rev Immunol 5(6):435–445. doi:10.1038/nri1629
Kaileh M, Sen R (2012) NF-kappaB function in B lymphocytes. Immunol Rev 246(1):254–271. doi:10.1111/j.1600-065X.2012.01106.x
Castro I, Wright JA, Damdinsuren B, Hoek KL, Carlesso G, Shinners NP, Gerstein RM, Woodland RT, Sen R, Khan WN (2009) B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2. J Immunol 182(12):7729–7737. doi:10.4049/jimmunol.0803281
Smith SH, Cancro MP (2003) Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors. J Immunol 170(12):5820–5823
Pillai S, Cariappa A (2009) The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol 9(11):767–777. doi:10.1038/nri2656
Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30:429–457. doi:10.1146/annurev-immunol-020711-075032
Mora AL, Stanley S, Armistead W, Chan AC, Boothby M (2001) Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappaB/Rel. J Immunol 167(10):5628–5635
Oh H, Ghosh S (2013) NF-kappaB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev 252(1):41–51. doi:10.1111/imr.12033
Long M, Park SG, Strickland I, Hayden MS, Ghosh S (2009) Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31(6):921–931. doi:10.1016/j.immuni.2009.09.022
Molinero LL, Cubre A, Mora-Solano C, Wang Y, Alegre ML (2012) T cell receptor/CARMA1/NF-kappaB signaling controls T-helper (Th) 17 differentiation. Proc Natl Acad Sci USA 109(45):18529–18534. doi:10.1073/pnas.1204557109
Yoshimura S, Bondeson J, Foxwell BM, Brennan FM, Feldmann M (2001) Effective antigen presentation by dendritic cells is NF-kappaB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines. Int Immunol 13(5):675–683. doi:10.1093/intimm/13.5.675
Gasparini C, Foxwell BM, Feldmann M (2009) RelB/p50 regulates CCL19 production, but fails to promote human DC maturation. Eur J Immunol 39(8):2215–2223. doi:10.1002/eji.200939209
Heel K, Tabone T, Rohrig KJ, Maslen PG, Meehan K, Grimwade LF, Erber WN (2013) Developments in the immunophenotypic analysis of haematological malignancies. Blood Rev 27(4):193–207. doi:10.1016/j.blre.2013.06.005
Rodriguez-Abreu D, Bordoni A, Zucca E (2007) Epidemiology of hematological malignancies. Ann Oncol 18(Suppl 1):i3–i8. doi:10.1093/annonc/mdl443
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117(19):5019–5032. doi:10.1182/blood-2011-01-293050
Braggio E, Egan JB, Fonseca R, Stewart AK (2013) Lessons from next-generation sequencing analysis in hematological malignancies. Blood Cancer J 3:e127. doi:10.1038/bcj.2013.26
Rampal R, Levine RL (2013) Leveraging cancer genome information in hematologic malignancies. J Clin Oncol 31(15):1885–1892. doi:10.1200/JCO.2013.48.7447
Brown CM, Larsen SR, Iland HJ, Joshua DE, Gibson J (2012) Leukaemias into the 21st century: part 1: the acute leukaemias. Intern Med J 42(11):1179–1186. doi:10.1111/j.1445-5994.2012.02938.x
Gibson J, Iland HJ, Larsen SR, Brown CM, Joshua DE (2013) Leukaemias into the 21st century. Part 2: the chronic leukaemias. Intern Med J 43(5):484–494. doi:10.1111/imj.12135
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503–511. doi:10.1038/35000501
Rajkumar SV (2009) Multiple myeloma. Curr Probl Cancer 33(1):7–64. doi:10.1016/j.currproblcancer.2009.01.001
Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374(9686):324–339. doi:10.1016/S0140-6736(09)60221-X
Jaffe ES (2009) The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology (Am Soc Hematol Educ Program):523–531. doi:10.1182/asheducation-2009.1.523
Shaffer AL 3rd, Young RM, Staudt LM (2012) Pathogenesis of human B cell lymphomas. Annu Rev Immunol 30:565–610. doi:10.1146/annurev-immunol-020711-075027
Nogai H, Dorken B, Lenz G (2011) Pathogenesis of non-Hodgkin’s lymphoma. J Clin Oncol 29(14):1803–1811. doi:10.1200/JCO.2010.33.3252
Rui L, Schmitz R, Ceribelli M, Staudt LM (2011) Malignant pirates of the immune system. Nat Immunol 12(10):933–940. doi:10.1038/ni.2094
Jost PJ, Ruland J (2007) Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 109(7):2700–2707. doi:10.1182/blood-2006-07-025809
Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR (2008) NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 15(4):391–399. doi:10.1097/MOH.0b013e328302c7f4
Braun T, Carvalho G, Coquelle A, Vozenin MC, Lepelley P, Hirsch F, Kiladjian JJ, Ribrag V, Fenaux P, Kroemer G (2006) NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome. Blood 107(3):1156–1165. doi:10.1182/blood-2005-05-1989
Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98(8):2301–2307. doi:10.1182/blood.V98.8.2301
Shanmugam R, Gade P, Wilson-Weekes A, Sayar H, Suvannasankha A, Goswami C, Li L, Gupta S, Cardoso AA, Al Baghdadi T, Sargent KJ, Cripe LD, Kalvakolanu DV, Boswell HS (2012) A noncanonical Flt3ITD/NF-kappaB signaling pathway represses DAPK1 in acute myeloid leukemia. Clin Cancer Res 18(2):360–369. doi:10.1158/1078-0432.CCR-10-3022
Suhasini M, Reddy CD, Reddy EP, DiDonato JA, Pilz RB (1997) cAMP-induced NF-kappaB (p50/relB) binding to a c-myb intronic enhancer correlates with c-myb up-regulation and inhibition of erythroleukemia cell differentiation. Oncogene 15(15):1859–1870. doi:10.1038/sj.onc.1201530
Suhasini M, Pilz RB (1999) Transcriptional elongation of c-myb is regulated by NF-kappaB (p50/RelB). Oncogene 18(51):7360–7369. doi:10.1038/sj.onc.1203158
Kirchner D, Duyster J, Ottmann O, Schmid RM, Bergmann L, Munzert G (2003) Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol 31(6):504–511. doi:10.1016/S0301-472X(03)00069-9
Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C (2000) Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14(3):399–402. doi:10.1038/sj.leu.2401705
Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, Kee BL, Ferrando A, Miele L, Aifantis I (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13(1):70–77. doi:10.1038/nm1524
Liu Z, Hazan-Halevy I, Harris DM, Li P, Ferrajoli A, Faderl S, Keating MJ, Estrov Z (2011) STAT-3 activates NF-kappaB in chronic lymphocytic leukemia cells. Mol Cancer Res 9(4):507–515. doi:10.1158/1541-7786.MCR-10-0559
Xu J, Zhou P, Wang W, Sun A, Guo F (2013) RelB, together with RelA, sustains cell survival and confers proteasome inhibitor sensitivity of chronic lymphocytic leukemia cells from bone marrow. J Mol Med (Berl). doi:10.1007/s00109-013-1081-6
Mineva ND, Rothstein TL, Meyers JA, Lerner A, Sonenshein GE (2007) CD40 ligand-mediated activation of the de novo RelB NF-kappaB synthesis pathway in transformed B cells promotes rescue from apoptosis. J Biol Chem 282(24):17475–17485. doi:10.1074/jbc.M607313200
Mori N, Fujii M, Ikeda S, Yamada Y, Tomonaga M, Ballard DW, Yamamoto N (1999) Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. Blood 93(7):2360–2368
Sun SC, Yamaoka S (2005) Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene 24(39):5952–5964. doi:10.1038/sj.onc.1208969
Isogawa M, Higuchi M, Takahashi M, Oie M, Mori N, Tanaka Y, Aoyagi Y, Fujii M (2008) Rearranged NF-kappa B2 gene in an adult T-cell leukemia cell line. Cancer Sci 99(4):792–798. doi:10.1111/j.1349-7006.2008.00750.x
Ohsugi T, Ishida T, Shimasaki T, Okada S, Umezawa K (2013) p53 dysfunction precedes the activation of nuclear factor-kappaB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein. Carcinogenesis 34(9):2129–2136. doi:10.1093/carcin/bgt144
Demchenko YN, Kuehl WM (2010) A critical role for the NFkB pathway in multiple myeloma. Oncotarget 1(1):59–68
Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Decaillet C, Grau M, Dorken B, Lenz P, Lenz G, Thome M (2011) Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci USA 108(35):14596–14601. doi:10.1073/pnas.1105020108
Calado DP, Zhang B, Srinivasan L, Sasaki Y, Seagal J, Unitt C, Rodig S, Kutok J, Tarakhovsky A, Schmidt-Supprian M, Rajewsky K (2010) Constitutive canonical NF-kappaB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell 18(6):580–589. doi:10.1016/j.ccr.2010.11.024
Ranuncolo SM, Pittaluga S, Evbuomwan MO, Jaffe ES, Lewis BA (2012) Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood 120(18):3756–3763. doi:10.1182/blood-2012-01-405951
Nonaka M, Horie R, Itoh K, Watanabe T, Yamamoto N, Yamaoka S (2005) Aberrant NF-kappaB2/p52 expression in Hodgkin/Reed–Sternberg cells and CD30-transformed rat fibroblasts. Oncogene 24(24):3976–3986. doi:10.1038/sj.onc.1208564
Guo F, Sun A, Wang W, He J, Hou J, Zhou P, Chen Z (2009) TRAF1 is involved in the classical NF-kappaB activation and CD30-induced alternative activity in Hodgkin’s lymphoma cells. Mol Immunol 46(13):2441–2448. doi:10.1016/j.molimm.2009.05.178
Schwarzer R, Dorken B, Jundt F (2012) Notch is an essential upstream regulator of NF-kappaB and is relevant for survival of Hodgkin and Reed–Sternberg cells. Leukemia 26(4):806–813. doi:10.1038/leu.2011.265
Wright CW, Rumble JM, Duckett CS (2007) CD30 activates both the canonical and alternative NF-kappaB pathways in anaplastic large cell lymphoma cells. J Biol Chem 282(14):10252–10262. doi:10.1074/jbc.M608817200
Mathas S, Johrens K, Joos S, Lietz A, Hummel F, Janz M, Jundt F, Anagnostopoulos I, Bommert K, Lichter P, Stein H, Scheidereit C, Dorken B (2005) Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 106(13):4287–4293. doi:10.1182/blood-2004-09-3620
Klapproth K, Sander S, Marinkovic D, Baumann B, Wirth T (2009) The IKK2/NF-(kappa)B pathway suppresses MYC-induced lymphomagenesis. Blood 114(12):2448–2458. doi:10.1182/blood-2008-09-181008
Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, Dave S, Hurt EM, Tan B, Zhao H, Stephens O, Santra M, Williams DR, Dang L, Barlogie B, Shaughnessy JD Jr, Kuehl WM, Staudt LM (2007) Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12(2):115–130. doi:10.1016/j.ccr.2007.07.004
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, Braggio E, Henry T, Zhu YX, Fogle H, Price-Troska T, Ahmann G, Mancini C, Brents LA, Kumar S, Greipp P, Dispenzieri A, Bryant B, Mulligan G, Bruhn L, Barrett M, Valdez R, Trent J, Stewart AK, Carpten J, Bergsagel PL (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12(2):131–144. doi:10.1016/j.ccr.2007.07.003
Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL, Kuehl WM (2010) Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood 115(17):3541–3552. doi:10.1182/blood-2009-09-243535
Cormier F, Monjanel H, Fabre C, Billot K, Sapharikas E, Chereau F, Bordereaux D, Molina TJ, Avet-Loiseau H, Baud V (2013) Frequent engagement of RelB activation is critical for cell survival in multiple myeloma. PLoS ONE 8(3):e59127. doi:10.1371/journal.pone.0059127
Landowski TH, Olashaw NE, Agrawal D, Dalton WS (2003) Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene 22(16):2417–2421. doi:10.1038/sj.onc.1206315
Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, Miller TP, LeBlanc M, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, Montserrat E, Wilson WH, Jaffe ES, Simon R, Yang L, Powell J, Zhao H, Goldschmidt N, Chiorazzi M, Staudt LM (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21):2159–2169. doi:10.1056/NEJMoa041869
dos Santos NR, Williame M, Gachet S, Cormier F, Janin A, Weih D, Weih F, Ghysdael J (2008) RelB-dependent stromal cells promote T-cell leukemogenesis. PLoS One 3(7):e2555. doi:10.1371/journal.pone.0002555
Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117(2):563–574. doi:10.1182/blood-2010-05-284984
Marienfeld R, May MJ, Berberich I, Serfling E, Ghosh S, Neumann M (2003) RelB forms transcriptionally inactive complexes with RelA/p65. J Biol Chem 278(22):19852–19860. doi:10.1074/jbc.M301945200
Gasparini C, Foxwell BM, Feldmann M (2013) RelB/p50 regulates TNF production in LPS-stimulated dendritic cells and macrophages. Cytokine 61(3):736–740. doi:10.1016/j.cyto.2012.12.029
Jacque E, Billot K, Authier H, Bordereaux D, Baud V (2012) RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation. Oncogene. doi:10.1038/onc.2012.282
Baldwin AS (2012) Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer. Immunol Rev 246(1):327–345. doi:10.1111/j.1600-065X.2012.01095.x
Johnson RF, Perkins ND (2012) Nuclear factor-kappaB, p53, and mitochondria: regulation of cellular metabolism and the Warburg effect. Trends Biochem Sci 37(8):317–324. doi:10.1016/j.tibs.2012.04.002
Secchiero P, Bosco R, Celeghini C, Zauli G (2011) Recent advances in the therapeutic perspectives of Nutlin-3. Curr Pharm Des 17(6):569–577. doi:10.2174/138161211795222586
Tergaonkar V, Pando M, Vafa O, Wahl G, Verma I (2002) p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell 1(5):493–503. doi:10.1016/S1535-6108(02)00068-5
Webster GA, Perkins ND (1999) Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol 19(5):3485–3495
Huang WC, Ju TK, Hung MC, Chen CC (2007) Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell 26(1):75–87. doi:10.1016/j.molcel.2007.02.019
Fujioka S, Schmidt C, Sclabas GM, Li Z, Pelicano H, Peng B, Yao A, Niu J, Zhang W, Evans DB, Abbruzzese JL, Huang P, Chiao PJ (2004) Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB. J Biol Chem 279(26):27549–27559. doi:10.1074/jbc.M313435200
Shetty S, Graham BA, Brown JG, Hu X, Vegh-Yarema N, Harding G, Paul JT, Gibson SB (2005) Transcription factor NF-kappaB differentially regulates death receptor 5 expression involving histone deacetylase 1. Mol Cell Biol 25(13):5404–5416. doi:10.1128/MCB.25.13.5404- 5416.2005
Jacque E, Billot K, Authier H, Bordereaux D, Baud V (2013) RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation. Oncogene 32(21):2661–2669. doi:10.1038/onc.2012.282
Schumm K, Rocha S, Caamano J, Perkins ND (2006) Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit. EMBO J 25(20):4820–4832. doi:10.1038/sj.emboj.7601343
Kiaris H, Chatzistamou I, Trimis G, Frangou-Plemmenou M, Pafiti-Kondi A, Kalofoutis A (2005) Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. Cancer Res 65(5):1627–1630. doi:10.1158/0008-5472.CAN-04-3791
Moskovits N, Kalinkovich A, Bar J, Lapidot T, Oren M (2006) p53 attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res 66(22):10671–10676. doi:10.1158/0008-5472.CAN-06-2323
Baud V, Karin M (2009) Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 8(1):33–40. doi:10.1038/nrd2781
Chu TC, Twu KY, Ellington AD, Levy M (2006) Aptamer mediated siRNA delivery. Nucleic Acids Res 34(10):e73. doi:10.1093/nar/gkl388
Gasparini C, Vecchi Brumatti L, Monasta L, Zauli G (2013) TRAIL-based therapeutic approaches for the treatment of pediatric malignancies. Curr Med Chem 20(17):2254–2271. doi:10.2174/0929867311320170009
Secchiero P, Zauli G (2008) Tumor-necrosis-factor-related apoptosis-inducing ligand and the regulation of hematopoiesis. Curr Opin Hematol 15(1):42–48. doi:10.1097/MOH.0b013e3282f15fa6
Secchiero P, Melloni E, Corallini F, Beltrami AP, Alviano F, Milani D, D’Aurizio F, di Iasio MG, Cesselli D, Bagnara GP, Zauli G (2008) Tumor necrosis factor-related apoptosis-inducing ligand promotes migration of human bone marrow multipotent stromal cells. Stem Cells 26(11):2955–2963. doi:10.1634/stemcells.2008-0512
Secchiero P, di Iasio MG, Gonelli A, Zauli G (2008) The MDM2 inhibitor Nutlins as an innovative therapeutic tool for the treatment of haematological malignancies. Curr Pharm Des 14(21):2100–2110. doi:10.2174/138161208785294663
Secchiero P, Zerbinati C, Melloni E, Milani D, Campioni D, Fadda R, Tiribelli M, Zauli G (2007) The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts. Neoplasia 9(10):853–861. doi:10.1593/neo.07523
Secchiero P, Melloni E, di Iasio MG, Tiribelli M, Rimondi E, Corallini F, Gattei V, Zauli G (2009) Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism. Blood 113(18):4300–4308. doi:10.1182/blood-2008-11-187708
Secchiero P, Corallini F, Rimondi E, Chiaruttini C, di Iasio MG, Rustighi A, Del Sal G, Zauli G (2008) Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells. Blood 111(3):1287–1294. doi:10.1182/blood-2007-05-092031
Zauli G, Melloni E, Capitani S, Secchiero P (2009) Role of full-length osteoprotegerin in tumor cell biology. Cell Mol Life Sci 66(5):841–851. doi:10.1007/s00018-008-8536-x
Gasparini C, Tommasini A, Zauli G (2012) The MDM2 inhibitor Nutlin-3 modulates dendritic cell-induced T cell proliferation. Hum Immunol 73(4):342–345. doi:10.1016/j.humimm.2012.01.018
Travert M, Ame-Thomas P, Pangault C, Morizot A, Micheau O, Semana G, Lamy T, Fest T, Tarte K, Guillaudeux T (2008) CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL. J Immunol 181(2):1001–1011
Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, Bartoli A, Coaccioli S, Screpanti I, Marconi P (2009) Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113(4):856–865. doi:10.1182/blood-2008-02-139725
Hertlein E, Byrd JC (2010) Signalling to drug resistance in CLL. Best Prac Res Clin Haematol 23(1):121–131. doi:10.1016/j.beha.2010.01.007
Romano MF, Lamberti A, Tassone P, Alfinito F, Costantini S, Chiurazzi F, Defrance T, Bonelli P, Tuccillo F, Turco MC, Venuta S (1998) Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 92(3):990–995
Perez LE, Parquet N, Meads M, Anasetti C, Dalton W (2010) Bortezomib restores stroma-mediated APO2L/TRAIL apoptosis resistance in multiple myeloma. Eur J Haematol 84(3):212–222. doi:10.1111/j.1600-0609.2009.01381.x
Jin L, Tabe Y, Kojima K, Zhou Y, Pittaluga S, Konopleva M, Miida T, Raffeld M (2010) MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma. Cancer Lett 299(2):161–170. doi:10.1016/j.canlet.2010.08.015
Saha MN, Jiang H, Jayakar J, Reece D, Branch DR, Chang H (2010) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9(11):936–944. doi:10.4161/cbt.9.11.11882
Ooi MG, Hayden PJ, Kotoula V, McMillin DW, Charalambous E, Daskalaki E, Raje NS, Munshi NC, Chauhan D, Hideshima T, Buon L, Clynes M, O’Gorman P, Richardson PG, Mitsiades CS, Anderson KC, Mitsiades N (2009) Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clin Cancer Res 15(23):7153–7160. doi:10.1158/1078-0432.CCR-09-1071
Conticello C, Adamo L, Vicari L, Giuffrida R, Iannolo G, Anastasi G, Caruso L, Moschetti G, Cupri A, Palumbo GA, Gulisano M, De Maria R, Giustolisi R, Di Raimondo F (2008) Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia. Acta Haematol 120(1):19–30. doi:10.1159/000151511
Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson SB (2006) The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis 11(7):1175–1193. doi:10.1007/s10495-006-8048-9
Di Pietro R, Zauli G (2004) Emerging non-apoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L. J Cell Physiol 201(3):331–340. doi:10.1002/jcp.20099
Zauli G, Sancilio S, Cataldi A, Sabatini N, Bosco D, Di Pietro R (2005) PI-3K/Akt and NF-kappaB/IkappaBalpha pathways are activated in Jurkat T cells in response to TRAIL treatment. J Cell Physiol 202(3):900–911. doi:10.1002/jcp.20202
Acknowledgments
We thank Dr. Fabio Rosso for the artwork of this review.
Conflict of interest
The authors declare no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gasparini, C., Celeghini, C., Monasta, L. et al. NF-κB pathways in hematological malignancies. Cell. Mol. Life Sci. 71, 2083–2102 (2014). https://doi.org/10.1007/s00018-013-1545-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-013-1545-4