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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (4) : 374-386
Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells
Sumedha Roy(), Yuan Zhuang
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
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A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt’s lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

Keywords Id proteins      lymphoma      leukemia      T cells      B cells      tumor suppressor      oncogene     
Corresponding Authors: Sumedha Roy   
Just Accepted Date: 09 July 2018   Online First Date: 25 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Sumedha Roy,Yuan Zhuang. Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells[J]. Front. Med., 2018, 12(4): 374-386.
Fig.1  Factors that influence context-dependent roles of E and Id proteins in development and cancer.
1 Norton JD, Deed RW, Craggs G, Sablitzky F. Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol 1998; 8(2): 58–65
pmid: 9695810
2 Lasorella A, Uo T, Iavarone A. Id proteins at the cross-road of development and cancer. Oncogene 2001; 20(58): 8326–8333 pmid: 11840325
3 Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM. Id proteins in cell growth and tumorigenesis. Cancer Cell 2003; 3(6): 525–530 pmid: 12842081
4 Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 2005; 5(8): 603–614 pmid: 16034366
5 Lasorella A, Benezra R, Iavarone A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer 2014; 14(2): 77–91 pmid: 24442143
6 Hasskarl J, Münger K. Id proteins—tumor markers or oncogenes? Cancer Biol Ther 2002; 1(2): 91–96 pmid: 12170780
7 Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal 2017; 15(1): 7 pmid: 28122577
8 Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 1990; 61(1): 49–59 pmid: 2156629
9 Langlands K, Yin X, Anand G, Prochownik EV. Differential interactions of Id proteins with basic-helix-loop-helix transcription factors. J Biol Chem 1997; 272(32): 19785–19793 pmid: 9242638
10 Israel MA, Hernandez MC, Florio M, Andres-Barquin PJ, Mantani A, Carter JH, Julin CM. Id gene expression as a key mediator of tumor cell biology. Cancer Res 1999; 59(7 Suppl): 1726s–1730s
pmid: 10197587
11 Norton JD, Atherton GT. Coupling of cell growth control and apoptosis functions of Id proteins. Mol Cell Biol 1998; 18(4): 2371–2381 pmid: 9528806
12 Wong YC, Wang X, Ling MT. Id-1 expression and cell survival. Apoptosis 2004; 9(3): 279–289 pmid: 15258459
13 Engel I, Murre C. E2A proteins enforce a proliferation checkpoint in developing thymocytes. EMBO J 2004; 23(1): 202–211 pmid: 14685278
14 Slattery C, Ryan MP, McMorrow T. E2A proteins: regulators of cell phenotype in normal physiology and disease. Int J Biochem Cell Biol 2008; 40(8): 1431–1436 pmid: 17604208
15 Tang J, Gordon GM, Nickoloff BJ, Foreman KE. The helix-loop-helix protein Id-1 delays onset of replicative senescence in human endothelial cells. Lab Invest 2002; 82(8): 1073–1079 pmid: 12177246
16 Neuhold LA, Wold B. HLH forced dimers: tethering MyoD to E47 generates a dominant positive myogenic factor insulated from negative regulation by Id. Cell 1993; 74(6): 1033–1042 pmid: 7691411
17 Deed RW, Armitage S, Norton JD. Nuclear localization and regulation of Id protein through an E protein-mediated chaperone mechanism. J Biol Chem 1996; 271(39): 23603–23606 pmid: 8798572
18 Zhuang Y, Soriano P, Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell 1994; 79(5): 875–884 pmid: 8001124
19 Bain G, Maandag EC, Izon DJ, Amsen D, Kruisbeek AM, Weintraub BC, Krop I, Schlissel MS, Feeney AJ, van Roon M, van der Valk M, te Riele HPJ, Berns A, Murre C. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 1994; 79(5): 885–892 pmid: 8001125
20 Engel I, Johns C, Bain G, Rivera RR, Murre C. Early thymocyte development is regulated by modulation of E2A protein activity. J Exp Med 2001; 194(6): 733–745 pmid: 11560990
21 Greenbaum S, Zhuang Y. Regulation of early lymphocyte development by E2A family proteins. Semin Immunol 2002; 14(6): 405–414 pmid: 12457613
22 Zhuang Y, Jackson A, Pan L, Shen K, Dai M. Regulation of E2A gene expression in B-lymphocyte development. Mol Immunol 2004; 40(16): 1165–1177 pmid: 15104122
23 Greenbaum S, Zhuang Y. Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system. Proc Natl Acad Sci USA 2002; 99(23): 15030–15035 pmid: 12415115
24 Lin YC, Jhunjhunwala S, Benner C, Heinz S, Welinder E, Mansson R, Sigvardsson M, Hagman J, Espinoza CA, Dutkowski J, Ideker T, Glass CK, Murre C. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol 2010; 11(7): 635–643 pmid: 20543837
25 Murre C. Helix-loop-helix proteins and lymphocyte development. Nat Immunol 2005; 6(11): 1079–1086 pmid: 16239924
26 Miyazaki K, Miyazaki M, Murre C. The establishment of B versus T cell identity. Trends Immunol 2014; 35(5): 205–210 pmid: 24679436
27 Kwon K, Hutter C, Sun Q, Bilic I, Cobaleda C, Malin S, Busslinger M. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity 2008; 28(6): 751–762 pmid: 18538592
28 Herblot S, Aplan PD, Hoang T. Gradient of E2A activity in B-cell development. Mol Cell Biol 2002; 22(3): 886–900 pmid: 11784864
29 Kee BL, Rivera RR, Murre C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-β. Nat Immunol 2001; 2(3): 242–247 pmid: 11224524
30 Chen S, Miyazaki M, Chandra V, Fisch KM, Chang AN, Murre C. Id3 orchestrates germinal center b cell development. Mol Cell Biol 2016; 36(20): 2543–2552 pmid: 27457619
31 Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene 2001; 20(40): 5595–5610 pmid: 11607812
32 Miles RR, Raphael M, McCarthy K, Wotherspoon A, Lones MA, Terrier-Lacombe MJ, Patte C, Gerrard M, Auperin A, Sposto R, Davenport V, Cairo MS, Perkins SL; SFOP/LMB96/CCG5961/UKCCSG/NHL 9600 Study Group. Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 2008; 51(3): 369–374 pmid: 18493992
33 Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WW, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet 2012; 44(12): 1321–1325 pmid: 23143597
34 Richter J, Schlesner M, Hoffmann S, Kreuz M, Leich E, Burkhardt B, Rosolowski M, Ammerpohl O, Wagener R, Bernhart SH, Lenze D, Szczepanowski M, Paulsen M, Lipinski S, Russell RB, Adam-Klages S, Apic G, Claviez A, Hasenclever D, Hovestadt V, Hornig N, Korbel JO, Kube D, Langenberger D, Lawerenz C, Lisfeld J, Meyer K, Picelli S, Pischimarov J, Radlwimmer B, Rausch T, Rohde M, Schilhabel M, Scholtysik R, Spang R, Trautmann H, Zenz T, Borkhardt A, Drexler HG, Möller P, MacLeod RA, Pott C, Schreiber S, Trümper L, Loeffler M, Stadler PF, Lichter P, Eils R, Küppers R, Hummel M, Klapper W, Rosenstiel P, Rosenwald A, Brors B, Siebert R; ICGC MMML-Seq Project. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 2012; 44(12): 1316–1320 pmid: 23143595
35 Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, Wright G, Shaffer AL, Hodson DJ, Buras E, Liu X, Powell J, Yang Y, Xu W, Zhao H, Kohlhammer H, Rosenwald A, Kluin P, Müller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Ogwang MD, Reynolds SJ, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pittaluga S, Wilson W, Waldmann TA, Rowe M, Mbulaiteye SM, Rickinson AB, Staudt LM. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012; 490(7418): 116–120 pmid: 22885699
36 Havelange V, Pepermans X, Ameye G, Théate I, Callet-Bauchu E, Barin C, Penther D, Lippert E, Michaux L, Mugneret F, Dastugue N, Raphaël M, Vikkula M, Poirel HA. Genetic differences between paediatric and adult Burkitt lymphomas. Br J Haematol 2016; 173(1): 137–144 pmid: 26887776
37 Cato MH, Chintalapati SK, Yau IW, Omori SA, Rickert RC. Cyclin D3 is selectively required for proliferative expansion of germinal center B cells. Mol Cell Biol 2011; 31(1): 127–137 pmid: 20956554
38 Peled JU, Yu JJ, Venkatesh J, Bi E, Ding BB, Krupski-Downs M, Shaknovich R, Sicinski P, Diamond B, Scharff MD, Ye BH. Requirement for cyclin D3 in germinal center formation and function. Cell Res 2010; 20(6): 631–646 pmid: 20404856
39 Rohde M, Bonn BR, Zimmermann M, Lange J, Möricke A, Klapper W, Oschlies I, Szczepanowski M, Nagel I, Schrappe M; MMML-MYC-SYS Project; ICGC MMML-Seq Project, Loeffler M, Siebert R, Reiter A, Burkhardt B. Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols. Haematologica 2017; 102(6): 1091–1098 pmid: 28209658
40 Kee BLE. E and ID proteins branch out. Nat Rev Immunol 2009; 9(3): 175–184 pmid: 19240756
41 Roschke V, Kopantzev E, Dertzbaugh M, Rudikoff S. Chromosomal translocations deregulating c-myc are associated with normal immune responses. Oncogene 1997; 14(25): 3011–3016 pmid: 9223664
42 Nepal RM, Zaheen A, Basit W, Li L, Berger SA, Martin A. AID and RAG1 do not contribute to lymphomagenesis in Emu c-myc transgenic mice. Oncogene 2008; 27(34): 4752–4756 pmid: 18408759
43 Scholtysik R, Kreuz M, Klapper W, Burkhardt B, Feller AC, Hummel M, Loeffler M, Rosolowski M, Schwaenen C, Spang R, Stein H, Thorns C, Trümper L, Vater I, Wessendorf S, Zenz T, Siebert R, Küppers R; Molecular Mechanisms in Malignant Lymphomas Network Project of Deutsche Krebshilfe. Detection of genomic aberrations in molecularly defined Burkitt’s lymphoma by array-based, high resolution, single nucleotide polymorphism analysis. Haematologica 2010; 95(12): 2047–2055 pmid: 20823134
44 Salaverria I, Martin-Guerrero I, Wagener R, Kreuz M, Kohler CW, Richter J, Pienkowska-Grela B, Adam P, Burkhardt B, Claviez A, Damm-Welk C, Drexler HG, Hummel M, Jaffe ES, Küppers R, Lefebvre C, Lisfeld J, Löffler M, Macleod RA, Nagel I, Oschlies I, Rosolowski M, Russell RB, Rymkiewicz G, Schindler D, Schlesner M, Scholtysik R, Schwaenen C, Spang R, Szczepanowski M, Trümper L, Vater I, Wessendorf S, Klapper W, Siebert R; Molecular Mechanisms in Malignant Lymphoma Network Project; Berlin-Frankfurt-Münster Non-Hodgkin Lymphoma Group. A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 2014; 123(8): 1187–1198 pmid: 24398325
45 Campo E. New pathogenic mechanisms in Burkitt lymphoma. Nat Genet 2012; 44(12): 1288–1289 pmid: 23192177
46 Forshell LP, Li Y, Forshell TZ, Rudelius M, Nilsson L, Keller U, Nilsson J. The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas. Oncotarget 2011; 2(6): 448–460 pmid: 21646687
47 Murphy DJ, Swigart LB, Israel MA, Evan GI. Id2 is dispensable for Myc-induced epidermal neoplasia. Mol Cell Biol 2004; 24(5): 2083–2090 pmid: 14966287
48 Gao XZ, Zhao WG, Wang GN, Cui MY, Zhang YR, Li WC. Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2′-deoxycytosine with potential therapeutic significance in Burkitt’s lymphoma. Mol Med Rep 2016; 13(2): 1269–1274 pmid: 26648013
49 Spender LC, Inman GJ. TGF-β induces growth arrest in Burkitt lymphoma cells via transcriptional repression of E2F-1. J Biol Chem 2009; 284(3): 1435–1442 pmid: 19022773
50 Bakkebø M, Huse K, Hilden VI, Smeland EB, Oksvold MP. TGF-β-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK. BMC Immunol 2010; 11(1): 57 pmid: 21092277
51 Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Norgaard P, Pedersen M, Gang AO, Hogdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, and Dave SS. Genetic and functional drivers of diffuse large B cell lymphoma. Cell 2017; 171(2): p. 481–494e15
52 Dubois S, Viailly PJ, Mareschal S, Bohers E, Bertrand P, Ruminy P, Maingonnat C, Jais JP, Peyrouze P, Figeac M, Molina TJ, Desmots F, Fest T, Haioun C, Lamy T, Copie-Bergman C, Brière J, Petrella T, Canioni D, Fabiani B, Coiffier B, Delarue R, Peyrade F, Bosly A, André M, Ketterer N, Salles G, Tilly H, Leroy K, Jardin F. Next-generation sequencing in diffuse large B-cell lymphoma highlights molecular divergence and therapeutic opportunities: a LYSA study. Clin Cancer Res 2016; 22(12): 2919–2928 pmid: 26819451
53 Momose S, Weißbach S, Pischimarov J, Nedeva T, Bach E, Rudelius M, Geissinger E, Staiger AM, Ott G, Rosenwald A. The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum. Leukemia 2015; 29(8): 1789–1791 pmid: 25673238
54 Gebauer N, Bernard V, Feller AC, Merz H. ID3 mutations are recurrent events in double-hit B-cell lymphomas. Anticancer Res 2013; 33(11): 4771–4778
pmid: 24222112
55 Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Müller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med 2006; 354(23): 2431–2442 pmid: 16760443
56 Recaldin T, Fear DJ. Transcription factors regulating B cell fate in the germinal centre. Clin Exp Immunol 2016; 183(1): 65–75 pmid: 26352785
57 Ramezani-Rad P, Rickert RC. Murine models of germinal center derived-lymphomas. Curr Opin Immunol 2017; 45: 31–36 pmid: 28160624
58 Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol 2015; 15(3): 172–184 pmid: 25712152
59 Dorsett Y, Robbiani DF, Jankovic M, Reina-San-Martin B, Eisenreich TR, Nussenzweig MC. A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med 2007; 204(9): 2225–2232 pmid: 17724134
60 Pasqualucci LBhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, Honjo T, Morse HC, Nussenzweig MC 3rd, Dalla-Favera R. AID is required for germinal center-derived lymphomagenesis. Nat Genet 2008; 40(1): 108–112 pmid: 18066064
61 Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 2012; 120(11): 2240–2248 pmid: 22740445
62 Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med 2014; 4(2): a014282 pmid: 24492847
63 Gloury R, Zotos D, Zuidscherwoude M, Masson F, Liao Y, Hasbold J, Corcoran LM, Hodgkin PD, Belz GT, Shi W, Nutt SL, Tarlinton DM, Kallies A. Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development. J Exp Med 2016; 213(6): 1095–1111 pmid: 27217539
64 Calado DP, Sasaki Y, Godinho SA, Pellerin A, Köchert K, Sleckman BP, de Alborán IM, Janz M, Rodig S, Rajewsky K. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol 2012; 13(11): 1092–1100 pmid: 23001146
65 Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M, Nussenzweig MC, Dalla-Favera R. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol 2012; 13(11): 1083–1091 pmid: 23001145
66 Bemark M, Neuberger MS. By-products of immunoglobulin somatic hypermutation. Genes Chromosomes Cancer 2003; 38(1): 32–39 pmid: 12874784
67 Guikema JE, de Boer C, Haralambieva E, Smit LA, van Noesel CJ, Schuuring E, Kluin PM. IGH switch breakpoints in Burkitt lymphoma: exclusive involvement of noncanonical class switch recombination. Genes Chromosomes Cancer 2006; 45(9): 808–819 pmid: 16736499
68 Xu Z, Pone EJ, Al-Qahtani A, Park SR, Zan H, Casali P. Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination. Crit Rev Immunol 2007; 27(4): 367–397 pmid: 18197815
69 Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev 2012; 247(1): 172–183 pmid: 22500840
70 Cruz-Rodriguez N, Combita AL, Enciso LJ, Raney LF, Pinzon PL, Lozano OC, Campos AM, Peñaloza N, Solano J, Herrera MV, Zabaleta J, Quijano S. Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL. J Exp Clin Cancer Res 2017; 36(1): 37 pmid: 28245840
71 Bellido M, Aventín A, Lasa A, Estivill C, Carnicer MJ, Pons C, Matías-Guiu X, Bordes R, Baiget M, Sierra J, Nomdedéu JF. Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia. Haematologica 2003; 88(9): 994–1001
pmid: 12969807
72 Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, Shen Q, Chadburn A, Rajewsky K, Tarakhovsky A, Pasqualucci L, Dalla-Favera R. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell 2010; 18(6): 568–579 pmid: 21156281
73 Husson H, Carideo EG, Neuberg D, Schultze J, Munoz O, Marks PW, Donovan JW, Chillemi AC, O’Connell P, Freedman AS. Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays. Blood 2002; 99(1): 282–289 pmid: 11756183
74 Renné C, Martin-Subero JI, Eickernjäger M, Hansmann ML, Küppers R, Siebert R, Bräuninger A. Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin’s lymphoma. Am J Pathol 2006; 169(2): 655–664 pmid: 16877363
75 Mathas S, Janz M, Hummel F, Hummel M, Wollert-Wulf B, Lusatis S, Anagnostopoulos I, Lietz A, Sigvardsson M, Jundt F, Jöhrens K, Bommert K, Stein H, Dörken B. Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol 2006; 7(2): 207–215 pmid: 16369535
76 Küppers R, Bräuninger A. Reprogramming of the tumour B-cell phenotype in Hodgkin lymphoma. Trends Immunol 2006; 27(5): 203–205 pmid: 16563865
77 Zhao P, Lu Y, Liu L, Zhong M. Aberrant expression of ID2 protein and its correlation with EBV-LMP1 and P16(INK4A) in classical Hodgkin lymphoma in China. BMC Cancer 2008; 8(1): 379 pmid: 19099554
78 Ikeda JI, Wada N, Nojima S, Tahara S, Tsuruta Y, Oya K, Morii E. ID1 upregulation and FoxO3a downregulation by Epstein-Barr virus-encoded LMP1 in Hodgkin’s lymphoma. Mol Clin Oncol 2016; 5(5): 562–566 pmid: 27900085
79 Lietz A, Janz M, Sigvardsson M, Jundt F, Dörken B, Mathas S. Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis. Br J Haematol 2007; 137(4): 342–348 pmid: 17456056
80 Liu TY, Chen SU, Kuo SH, Cheng AL, Lin CW. E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response. Mod Pathol 2010; 23(11): 1507–1517 pmid: 20802470
81 Seidel MG, Look AT. E2A-HLF usurps control of evolutionarily conserved survival pathways. Oncogene 2001; 20(40): 5718–5725 pmid: 11607821
82 Yoshihara T, Inaba T, Shapiro LH, Kato JY, Look AT. E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF. Mol Cell Biol 1995; 15(6): 3247–3255 pmid: 7760820
83 Kamps MP, Baltimore D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol Cell Biol 1993; 13(1): 351–357 pmid: 8093327
84 Dedera DA, Waller EK, LeBrun DP, Sen-Majumdar A, Stevens ME, Barsh GS, Cleary ML. Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice. Cell 1993; 74(5): 833–843 pmid: 8104101
85 Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 1990; 60(4): 535–545 pmid: 1967982
86 Engel I, Murre C. The function of E- and Id proteins in lymphocyte development. Nat Rev Immunol 2001; 1(3): 193–199 pmid: 11905828
87 Murre C. Role of helix-loop-helix proteins in lymphocyte development. Cold Spring Harb Symp Quant Biol 1999; 64(0): 39–44 pmid: 11232313
88 Miyazaki M, Rivera RR, Miyazaki K, Lin YC, Agata Y, Murre C. The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 2011; 12(10): 992–1001 pmid: 21857655
89 Bain G, Engel I, Robanus Maandag EC, te Riele HP, Voland JR, Sharp LL, Chun J, Huey B, Pinkel D, Murre C. E2A deficiency leads to abnormalities in αβ T-cell development and to rapid development of T-cell lymphomas. Mol Cell Biol 1997; 17(8): 4782–4791 pmid: 9234734
90 Yan W, Young AZ, Soares VC, Kelley R, Benezra R, Zhuang Y. High incidence of T-cell tumors in E2A-null mice and E2A/Id1 double-knockout mice. Mol Cell Biol 1997; 17(12): 7317–7327 pmid: 9372963
91 Engel I, Murre C. Ectopic expression of E47 or E12 promotes the death of E2A-deficient lymphomas. Proc Natl Acad Sci USA 1999; 96(3): 996–1001 pmid: 9927682
92 Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q, Ferrando AA, Levin SD, Geng Y, von Boehmer H, Sicinski P. Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 2003; 4(6): 451–461 pmid: 14706337
93 Schwartz R, Engel I, Fallahi-Sichani M, Petrie HT, Murre C. Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development. Proc Natl Acad Sci USA 2006; 103(26): 9976–9981 pmid: 16782810
94 Steininger A, Möbs M, Ullmann R, Köchert K, Kreher S, Lamprecht B, Anagnostopoulos I, Hummel M, Richter J, Beyer M, Janz M, Klemke CD, Stein H, Dörken B, Sterry W, Schrock E, Mathas S, Assaf C. Genomic loss of the putative tumor suppressor gene E2A in human lymphoma. J Exp Med 2011; 208(8): 1585–1593 pmid: 21788410
95 Mathas S, Kreher S, Meaburn KJ, Jöhrens K, Lamprecht B, Assaf C, Sterry W, Kadin ME, Daibata M, Joos S, Hummel M, Stein H, Janz M, Anagnostopoulos I, Schrock E, Misteli T, Dörken B. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Proc Natl Acad Sci USA 2009; 106(14): 5831–5836 pmid: 19321746
96 O’Neil J, Shank J, Cusson N, Murre C, Kelliher M. TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell 2004; 5(6): 587–596 pmid: 15193261
97 Park ST, Nolan GP, Sun XH. Growth inhibition and apoptosis due to restoration of E2A activity in T cell acute lymphoblastic leukemia cells. J Exp Med 1999; 189(3): 501–508 pmid: 9927512
98 Sanda T, Lawton LN, Barrasa MI, Fan ZP, Kohlhammer H, Gutierrez A, Ma W, Tatarek J, Ahn Y, Kelliher MA, Jamieson CH, Staudt LM, Young RA, Look AT. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia. Cancer Cell 2012; 22(2): 209–221 pmid: 22897851
99 Tan SH, Yam AW, Lawton LN, Wong RW, Young RA, Look AT, Sanda T. TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia 2016; 30(4): 959–962 pmid: 26202930
100 Spaulding C, Reschly EJ, Zagort DE, Yashiro-Ohtani Y, Beverly LJ, Capobianco A, Pear WS, Kee BL. Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas. Blood 2007; 110(7): 2650–2658 pmid: 17585052
101 Wang HC, Peng V, Zhao Y, Sun XH. Enhanced Notch activation is advantageous but not essential for T cell lymphomagenesis in Id1 transgenic mice. PLoS One 2012; 7(2): e32944 pmid: 22393458
102 Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6(5): 347–359 pmid: 16612405
103 Reschly EJ, Spaulding C, Vilimas T, Graham WV, Brumbaugh RL, Aifantis I, Pear WS, Kee BL. Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and-independent mechanisms. Blood 2006; 107(10): 4115–4121 pmid: 16449526
104 Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M, Frati L, von Boehmer H, Gulino A, Screpanti I. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma. EMBO Rep 2003; 4(11): 1067–1072 pmid: 14566327
105 Cotta CV, Leventaki V, Atsaves V, Vidaki A, Schlette E, Jones D, Medeiros LJ, Rassidakis GZ. The helix-loop-helix protein Id2 is expressed differentially and induced by myc in T-cell lymphomas. Cancer 2008; 112(3): 552–561 pmid: 18085637
106 Morrow MA, Mayer EW, Perez CA, Adlam M, Siu G. Overexpression of the helix-loop-helix protein Id2 blocks T cell development at multiple stages. Mol Immunol 1999; 36(8): 491–503 pmid: 10475604
107 Kim D, Peng XC, Sun XH. Massive apoptosis of thymocytes in T-cell-deficient Id1 transgenic mice. Mol Cell Biol 1999; 19(12): 8240–8253 pmid: 10567549
108 Li J, Maruyama T, Zhang P, Konkel JE, Hoffman V, Zamarron B, Chen W. Mutation of inhibitory helix-loop-helix protein Id3 causes gd T-cell lymphoma in mice. Blood 2010; 116(25): 5615–5621 pmid: 20852128
109 Li J, Roy S, Kim YM, Li S, Zhang B, Love C, Reddy A, Rajagopalan D, Dave S, Diehl AM, Zhuang Y. Id2 collaborates with Id3 to suppress invariant NKT and innate-like tumors. J Immunol 2017; 198(8): 3136–3148 pmid: 28258199
110 Miyazaki M, Miyazaki K, Chen S, Chandra V, Wagatsuma K, Agata Y, Rodewald HR, Saito R, Chang AN, Varki N, Kawamoto H, Murre C. The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. Genes Dev 2015; 29(4): 409–425 pmid: 25691468
111 Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu YZ, Raval A, Liu TH, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA, Plass C. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 2005; 37(3): 265–274 pmid: 15723065
112 Chen SS, Claus R, Lucas DM, Yu L, Qian J, Ruppert AS, West DA, Williams KE, Johnson AJ, Sablitzky F, Plass C, Byrd JC. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL. Blood 2011; 117(3): 862–871 pmid: 21098398
113 Cen J, Shen J, Wang X, Kang H, Wang L, Sun L, Li Y, Yu L. Association between lymphoma prognosis and aberrant methylation of ID4 and ZO-1 in bone marrow and paraffin-embedded lymphoma tissues of treatment-naive patients. Oncol Rep 2013; 30(1): 455–461 pmid: 23670122
114 Hagiwara K, Nagai H, Li Y, Ohashi H, Hotta T, Saito H. Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma. J Clin Exp Hematop 2007; 47(1): 15–18 pmid: 17510533
115 Alani RM, Hasskarl J, Grace M, Hernandez MC, Israel MA, Münger K. Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1. Proc Natl Acad Sci USA 1999; 96(17): 9637–9641 pmid: 10449746
116 Nickoloff BJ, Chaturvedi V, Bacon P, Qin JZ, Denning MF, Diaz MO. Id-1 delays senescence but does not immortalize keratinocytes. J Biol Chem 2000; 275(36): 27501–27504
pmid: 10908559
117 Wöhner M, Tagoh H, Bilic I, Jaritz M, Poliakova DK, Fischer M, Busslinger M. Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development. J Exp Med 2016; 213(7): 1201–1221 pmid: 27261530
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