Hodgkin lymphoma

Blimp1/PRDM1

Oct-2 and Bob.1†

Oct-2(octamer-binding transcription factor2)*1*2*3*4*5

Oct-2-->NCBI geneのページ19q13.2に局在. 正式名：POU class 2 homeobox 2

OCT2の発現はB-cellおよび神経細胞に限られる.*6

B-cellにおいてはIg promoterの転写活性化に重要な役割をはたすことが実験でしめされている。またB-cell増殖・分化に重要なB細胞遺伝子, CD20, CD79a, Ig, J chainなどをコントロールしている。

BOB1--> HGNC official full name: POU2AF1 POU class 2 associating factor 1~局在は11q23.1

注意:腎近位尿細管の側底膜に発現する有機カチオントランスポータOCT2と混同しないこと。こちらもいろいろ注目されている

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classical Hodgkin's lymphoma(CHL)病理診断への応用*15*16*17*18†

HRS細胞はB細胞の形質を通常消失しており*20, B細胞リンパ腫および白血病の腫瘍細胞は由来となったB細胞の重要な形質および機能を保ちつづける*21という原則から逸脱した細胞といえる。

HRS cellがB細胞形質を喪失する再プログラミングには以下の3つの機序が関連している*22。

1. B細胞分子を阻害する分子の不規則な発現

  • ID2(inhibitor of differentiation and DNA binding2)：E2AにコードされたB細胞転写因子E12とE47に結合して,それらとDNAとの結合を阻害する
  • activated B-cell factor1(ABF1):ABF1とE12またはE47とのヘテロダイマーはDNAとの結合はまだできるがB-cell geneを活性化することはできない
  • notch1
    Notch1はE12, E47両方を阻害することができ, HRS cellで低レベルで発現しているearly B-cell factor(EBF)と、おそらくPAX5も阻害している
    Notch1の活性はホジキンリンパ腫微小環境に発現するリガンドにより仲介され, notch1 inhibitor のdeltex1により抑制される。

2. B細胞転写因子の減少, 下方制御(downregulation)

  • Oct2, BOB1, PU.1が減少あるいは消失する。

3. B-cell gene, CD19とimmunoglobulin H(IgH)のepigenetic silencing

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NLPHL (Nodular lymphocyte predominant Hodgkin lymphoma)†

NLPHLのL&H(lymphocytic and/or histiocytic cells)細胞では部分的なB細胞形質のdownregulationが認められる*23

L&H cellsではSOCS1, BCL6遺伝子変異を示す症例の頻度が高い*24。

14例のNLPHLの腫瘍性L&H細胞のまわりにはPD-1陽性T細胞がロゼットを形成して認められた。*25(T/Histiocyte-rich B-cell lymphomaの大型細胞まわりにはCD57ロゼットができることと比較できる？)

*1  Saez AI, et al., Analysis of octamer-binding transcriptor factors Oct2 and Oct1 and their coactivator BOB.1/OBF.1 in lymphomas. Mod Pathol 2002;15:211.220.
*2  Malone CS, et al. An upstream Oct-1 and Oct-2 binding silencer governsB29 (Ig beta) gene expression. J Immunol 2000;164:2550-2556.
*3  Pfisterer P, et al. CRISP-3, a protein with homology to plant defense proteins, is expressed in mouse B cells under the control of Oct2. Mol Cell Biol 1996;16:6160-6168.
*4  Thevenin C, et al. Cell type- and stage-specific expression of the CD20/B1 antigen correlates with the activity of a diverged octamer DNA motif present in its promoter. J Biol Chem 1993;268:5949-5956.
*5  Corcoran LM, Karvelas M. Oct2 is required early in T cell-independent B cell activation for G1 progression and for proliferation. Immunity 1994;1:635-645.
*6  Latchman DS.The Oct-2 transcription factor.Int J Biochem Cell Biol. 1996 Oct;28(10):1081-3.PMID:8930131
*7  Scholer HR. Octamania: the POU factors in murine development. Trends Genet. 1991;7:323-329.
*8  Theil J, Laumen H, Marafioti T, et al. Defective octamerdependent transcription is responsible for silenced immunoglobulin transcription in Reed-Sternberg cells. Blood. 2001;97:3191-3196.
*9  Chang JF, et al. Oct-1 POU and octamer DNA cooperate to recognize the Bob-1 transcription coactivator via induced folding. J Mol Biol. 1999;288:941-952.
*10  Laumen H, et al. The BOB.1/OBF.1 coactivator is essential for octamer-dependent transcription in B cells. Eur J Immunol. 2000;30:458-469.
*11  Stein H, et al. Down-regulation of BOB.1/OBF.1 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood. 2001;97:496-501.
*12  Re D, et al. Oct-2 and Bob-1 deficiency in Hodgkin and Reed-Sternberg cells. Cancer Res. 2001;61:2080-2084.
*13  Saez A-I, et al. Analysis of the octamer-binding transcription factors Oct2 and Oct1 and their coactivator BOB.1/OBF.1 in lymphomas. Mod Pathol. 2002;15:211-220.
*14  Tamaru J, et al, Hodgkin-like anaplastic large cell lymphoma (previously designated in the REAL classification) has same immunophenotypic features to classical Hodgkin lymphoma.Leuk Lymphoma. 2007 Jun;48(6):1127-38.PMID:17577776
*15  Stein H, et al. Down-regulation of BOB.1/OBF.1 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood. 2001;97:496-501.
*16  Re D, et al. Oct-2 and Bob-1 deficiency in Hodgkin and Reed-Sternberg cells. Cancer Res. 2001;61:2080-2084.
*17  Saez A-I, et al. Analysis of the octamer-binding transcription factors Oct2 and Oct1 and their coactivator BOB.1/OBF.1 in lymphomas. Mod Pathol. 2002;15:211-220.
*18  Tamaru J, et al, Hodgkin-like anaplastic large cell lymphoma (previously designated in the REAL classification) has same immunophenotypic features to classical Hodgkin lymphoma.Leuk Lymphoma. 2007 Jun;48(6):1127-38.PMID:17577776
*19  Elsayed AA, Asano N, et al. Prognostic significance of CD20 expression and Epstein-Barr virus (EBV) association in classical Hodgkin lymphoma in Japan: a clinicopathologic study. Pathol Int. 2014 Jul;64(7):336-45.
*20  Schwering, I. et al. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed- Sternberg cells of Hodgkin lymphoma. Blood 2003;101: 1505- 1512
*21  Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 2005; 5: 251- 262
*22  Küppers R. The biology of Hodgkin's lymphoma Nat Rev Cancer 2009; 9: 15-27
*23  Brune, V. et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J. Exp. Med. 2008;205: 2251- 2268
*24  文献Küppers R. The biology of Hodgkin's lymphoma Nat Rev Cancer 2009; 9: 15-27と同じ
*25  Dorfman DM, et al Programed Death-1(PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma Am J Surg Pathol 2006; 30(7): 802-810
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