2010-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/704686摘要：最近研究已顯示，淋巴結外B 細胞非何杰金氏淋巴癌，包括: 粘膜相關淋巴組織(MALT) 淋巴癌、瀰漫大型B 細胞淋巴癌(DLBCL)、和瀰漫大型B 細胞淋巴癌具粘膜相關淋巴組織來源(DLBCL[MALT])，其發生率已逐漸增加，並已超越淋巴結B 細胞非何杰金氏淋巴癌。最近我們已證實BCL10 和NF-B 兩個分子之細胞核轉位，是決定胃MALT 淋巴癌和胃DLBCL(MALT)之幽門桿菌非依賴性的關鍵，不論其是否具有t(1;14)(p22;q32) 和t(11;18)(q21;q21) (J Clin Oncol 2004;22:3491-7; Blood 2005;106:1037-41; J Pathol;2007;211:296-304). 除此之外，我們也發現BCL10 之核內轉位與其它非胃之MALT 淋巴癌的局部侵犯性和不好預後有高度相關。這重大發現經由我們最近的研究證實，即BCL10 之上調節(BCL10 核內轉位)，可藉由BCL10 之5’端非轉譯區域之NF-B 結合區域，參與TNF-所促進NF-B 活化之訊息傳遞路徑(J Biol Chem2006;281:167-75; Ann Surgery 2008;247:265-9)。除了TNF-之外，最近我們也證實BAFF (TNF 家族成員) 之過度表現與pAKT 表現、BCL10 和NF-B 之核內表現有高相關性，同時與胃DLBCL(MALT) 淋巴癌幽門桿菌非依賴性有高相關性(Blood 2008;112:2927-34)。在進一步的DLBCL 細胞株研究上，我們發現BAFF 可藉由古典路徑(BAFF/AKT/BCL10/NF-B) 和替代路徑(BAFF/NF-B2/p100/NF-B)來活化NF-B 和BCL10 細胞核轉位。很多研究證實，BAFF可向上調節抗凋零有關蛋白質表現，而促進淋巴癌細胞增殖。其它研究也顯示，人類之腦星突狀細胞(與原發性中樞性神經系統淋巴癌有關) 和骨髓基質細胞均可誘發BAFF產生，且BAFF 可功能性去促進B 淋巴癌細胞生長，並減少被細胞毒殺所導致凋零之機會。綜合這些研究結果，可見BAFF 所導致與發炎有關訊息傳遞，可經由淋巴癌細胞和其相鄰環境所產生，並進一步造成淋巴結外B 細胞非何杰金氏淋巴癌細胞過度生長。在之前的初步研究中，我們藉由FISH 染色方法證實染色體TRAF2 之異常複製，可發生在大部分無t(11;18)(q21;q21)轉位且為幽門桿菌非依賴性的胃MALT 淋巴癌患者。值得注意的是，在這些患者，其腫瘤細胞的TRAF2 蛋白質表現，與發生NF-B 和BAFF之核內轉位也高度相關。我們進一歩發現，everolimus (mTOR 之抑制劑) 可以抑制原發性MALT 淋巴癌細胞株和DLBCL 細胞株之成長，並抑制pAKT、p-mTOR、c-Myc、TNF-、和BAFF 表現，及BCL10 細胞核轉位和NF-B 轉錄活性。根據上述研究，我們推測持續的BAFF 活化，可藉由兩獨立之訊息傳遞路徑，即BAFF/TRAF2/NF-B和BAFF/AKT/mTOR，來促進淋巴結外B 細胞非何杰金氏淋巴癌的生長和存活。在本研究中，我們將善加利用我們之前經由前膽性和回朔性研究所收集之檢體來研究。同時，這些患者之臨床表徵，病理特徵和臨床預後均經過分析和品質化，適合我們進一步釐清，BAFF之訊息傳遞路徑，是否在淋巴結外B細胞非何杰金氏淋巴癌患者的分子機轉及生物意義，扮演極重要角色。我們主要的研究目的如下:(一) 進一歩釐清BAFF訊息傳遞路徑，在淋巴結外B細胞非何杰金氏淋巴癌致病機制中，所扮演其分子機轉及生物意義。(二) 探討造成有BAFF表現和無BAFF表現之兩組淋巴結外B細胞非何杰金氏淋巴癌的臨床表現和基因表現之差異性的關鍵基因，並分析這兩者之間的差異性。(三) 進一歩評估BAFF/BCL10/NF-B、BAFF/AKT/mTOR和BAFF/TRAF2/NF-B相關抑制劑及調節修飾BAFF訊息傳遞路徑之相關基因等方法，來治療淋巴結外B細胞非何杰金氏淋巴癌。我們相信此研究的成果將提升淋巴結外B 細胞非何杰金氏淋巴癌患者照護的品質，且幫助我們未來釐清BAFF 訊息傳遞路徑在淋巴結外B細胞非何杰金氏淋巴癌的致病分子機轉。<br> Abstract: It has been demonstrated that extranodal B-cell non-Hodgkin’s lymphoma (NHL),including MALT lymphoma, diffuse large cell B-cell lymphoma (DLBCL), and DLBCL withMALT origin (DLBCL[MALT]), increases more rapidly than nodal NHL. Recently, we havedemonstrated that nuclear translocation of BCL10 and NF-B is closely associated with the H.pylori-independent status of DLBCL(MALT) and MALT lymphoma of the stomach,irrespective of chromosome translocation of t(1;14)(p22;q32) and t(11;18)(q21;q21) (J ClinOncol 2004;22:3491-7; Blood 2005;106:1037-41; J Pathol;2007;211:296-304). In addition,we found that BCL10 nuclear translocation was closely associated with advanced stage andpoor prognosis of extra-gastric MALT lymphoma. These findings are supported by our recentobservation that up-regulation of BCL10 (BCL10 nuclear translocation) may be involved inthe TNF--activated NF-B signaling transduction pathway via an NF-B binding site in theBCL10 5’-untranslated region (J Biol Chem 2006;281:167-75; Ann Surgery 2008;247:265-9).In addition to TNF-, we have recently demonstrated that overexpression of BAFF isclosely associated with pAKT expression, nuclear translocation of BCL10, and NF-B, andthe H. pylori-independent status of gastric DLBCL(MALT) (Blood 2008;112:2927-34).Further exploration of the biological significance of these observations in DLBCL cellsreveals that BAFF activates NF-B and BCL10 nuclear translocation via the classicalpathway (BAFF/AKT/BCL10/NF-B) as well as an alternative pathway(BAFF/NF-B2/p100). Several studies have demonstrated that BAFF can up-regulateanti-apoptosis-related protein expression and promote the proliferation of lymphoma cells.Additional studies have shown that human astrocytes (primary central nervous systemlymphoma) and bone marrow stroma cells trigger BAFF secretion and functionally promotethe survival and attenuate cytotoxic apoptosis of B-cell lymphoma. Taken together, thesefindings indicate that BAFF-induced inflammation-related signal transduction, produced bytumor cells or tumor microenvironments, can contribute to the proliferation of extranodalB-cell NHLs.In preliminary report, we demonstrated that gain of additional copy of TRAF2, analyzedby interphase fluorescent in situ hybridyization (FISH), was found in the majority oft(11;18)(q21;q21)-negative H. pylori-independent gastric MALT lymphoma patients. Notably,protein expression of TRAF2 was closely associated with nuclear expression NF-B andBAFF in tumor cells of these patients. Furthermore, we demonstrated that everolimus (mTORinhibitor) induced growth inhibition in primary MALT lymphoma cell line and DLBCL cellline and suppressed the expression of pAKT, p-mTOR, c-Myc, TNF-, and BAFF, andnuclear expression of BCL10, and NF-B transactivity. These results suggest that constitutiveactivation BAFF may promote the survival and proliferation of extranodal B-cell NHL cellsthrough the activation of two independent signal transduction pathways,BAFF/TRAF2/NF-B and BAFF/AKT/mTOR.In this study, we will take advantage of the tumor specimens which we have collected inprospective studies and retrospective studies of extranodal B-cell NHLs. The clinicalcharacteristics and outcome of these patients have already been clarified and are suitable forcontinuing our effort in elucidating the molecular mechanisms and biologic significances ofthe BAFF-signal transduction pathway in these patients. Our specific aims are:(1) Continue exploration of the molecular mechanisms and biologic significance of theBAFF-signal transduction pathways in extranodal B-cell NHLs.(2) Exploration of the difference in the genetic expression and the clinical biologic behaviorof BAFF expression (+)- and BAFF expression (-)- extranodal B-cell NHLs.(3) Further evaluation of the efficacy of BAFF/BCL10/NF-B, BAFF/AKT/mTOR, andBAFF/TRAF2/NF-B inhibitors and modulation of BAFF -signaling related genes in thetreatment of extranodal B-cell NHLs.We believe this study will lead to better care of patients with extranodal B-cell NHLs,and help us to clarify the molecular mechanisms of BAFF-signal transduction pathways inextranodal B-cell NHLs in the future.淋巴結外BAFFBCL10NF-BTRAF2mTORextranodalBAFFBCL10NF-BTRAF2mTOR