Repression of TCF3/E2A Contributes to Hodgkin Lymphomagenesis

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 May 12

PMID 27166193

Citations 4

Authors

Hanfeng Guan

Linka Xie

Thomas Wirth

Alexey Ushmorov

Affiliations

Soon will be listed here.

Abstract

Although Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) derived from germinal or post germinal B cells, they have lost the B cell phenotype in the process of lymphomagenesis. The phenomenon can be at least partially explained by repression of B-cell-specific transcription factors including TCF3, early B-cell factor 1 (EBF1), SPI1/PU.1, and FOXO1, which are down-regulated by genetic and epigenetic mechanisms. The unique phenotype has been suspected to be advantageous for survival of HRS cells. Ectopic expression of some of these transcription factors (EBF1, PU.1, FOXO1) indeed impaired survival of cHL cells. Here we show that forced expression of TCF3 causes cell death and cell cycle arrest in cHL cell lines. Mechanistically, TCF3 overexpression modulated expression of multiple pro-apoptotic genes including BIK, APAF1, FASLG, BOK, and TNFRSF10A/DR4. We conclude that TCF3 inactivation contributes not only to extinguishing of B cell phenotype but also to cHL oncogenesis.

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References

Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B . Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002; 99(9):3398-403. DOI: 10.1182/blood.v99.9.3398. View

Yang Z, MacQuarrie K, Analau E, Tyler A, Dilworth F, Cao Y . MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state. Genes Dev. 2009; 23(6):694-707. PMC: 2661613. DOI: 10.1101/gad.1765109. View

Tiacci E, Doring C, Brune V, van Noesel C, Klapper W, Mechtersheimer G . Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood. 2012; 120(23):4609-20. DOI: 10.1182/blood-2012-05-428896. View

Mansson R, Welinder E, Ahsberg J, Lin Y, Benner C, Glass C . Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate. Proc Natl Acad Sci U S A. 2012; 109(51):21028-33. PMC: 3529039. DOI: 10.1073/pnas.1211427109. View

Iavarone A, Garg P, Lasorella A, Hsu J, Israel M . The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 1994; 8(11):1270-84. DOI: 10.1101/gad.8.11.1270. View

Hatzimichael E, Dasoula A, Kounnis V, Benetatos L, Lo Nigro C, Lattanzio L . Bcl2-interacting killer CpG methylation in multiple myeloma: a potential predictor of relapsed/refractory disease with therapeutic implications. Leuk Lymphoma. 2012; 53(9):1709-13. DOI: 10.3109/10428194.2012.661854. View

Park S, Nolan G, Sun X . Growth inhibition and apoptosis due to restoration of E2A activity in T cell acute lymphoblastic leukemia cells. J Exp Med. 1999; 189(3):501-8. PMC: 2192921. DOI: 10.1084/jem.189.3.501. View

Yan W, Young A, Soares V, 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):7317-27. PMC: 232588. DOI: 10.1128/MCB.17.12.7317. View

Brune V, Tiacci E, Pfeil I, Doring C, Eckerle S, van Noesel C . Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008; 205(10):2251-68. PMC: 2556780. DOI: 10.1084/jem.20080809. View

10.

Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A . Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature. 2000; 407(6804):592-8. DOI: 10.1038/35036504. View

11.

Prabhu S, Ignatova A, Park S, Sun X . Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol. 1997; 17(10):5888-96. PMC: 232436. DOI: 10.1128/MCB.17.10.5888. View

12.

Sale M, Cook S . The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G₁ cell-cycle arrest and not a direct effect on BIK protein stability. Biochem J. 2014; 459(3):513-24. DOI: 10.1042/BJ20131346. View

13.

Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A . A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell. 2012; 148(5):1001-14. DOI: 10.1016/j.cell.2012.01.040. View

14.

Mathas S, Janz M, Hummel F, Hummel M, Wollert-Wulf B, Lusatis S . Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol. 2005; 7(2):207-15. DOI: 10.1038/ni1285. View

15.

Steininger A, Mobs M, Ullmann R, Kochert K, Kreher S, Lamprecht B . Genomic loss of the putative tumor suppressor gene E2A in human lymphoma. J Exp Med. 2011; 208(8):1585-93. PMC: 3149217. DOI: 10.1084/jem.20101785. View

16.

Xie L, Ushmorov A, Leithauser F, Guan H, Steidl C, Farbinger J . FOXO1 is a tumor suppressor in classical Hodgkin lymphoma. Blood. 2012; 119(15):3503-11. DOI: 10.1182/blood-2011-09-381905. View

17.

Bain G, Engel I, Robanus Maandag E, te Riele H, Voland J, Sharp L . E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas. Mol Cell Biol. 1997; 17(8):4782-91. PMC: 232330. DOI: 10.1128/MCB.17.8.4782. View

18.

Shaffer A, Rosenwald A, Hurt E, Giltnane J, Lam L, Pickeral O . Signatures of the immune response. Immunity. 2001; 15(3):375-85. DOI: 10.1016/s1074-7613(01)00194-7. View

19.

Jiang A, Clark E . Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. J Immunol. 2001; 166(10):6025-33. DOI: 10.4049/jimmunol.166.10.6025. View

20.

Shaffer A, Emre N, Lamy L, Ngo V, Wright G, Xiao W . IRF4 addiction in multiple myeloma. Nature. 2008; 454(7201):226-31. PMC: 2542904. DOI: 10.1038/nature07064. View