Fu Lingchen, Lin-Lee Yen-Chiu, Pham Lan V, Tamayo Archito, Yoshimura Linda, Ford Richard J
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2006 Jun 1;107(11):4540-8. doi: 10.1182/blood-2005-10-4042. Epub 2006 Feb 23.
B-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-kappaB and NFAT, are involved in regulating BLyS expression through at least one NF-kappaB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-kappaB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.
B淋巴细胞刺激因子（BLyS）是肿瘤坏死因子配体家族（TNF）中一个相对较新发现的成员，是一种在许多造血细胞中表达的强效细胞存活因子。BLyS与3种TNF-R受体，即跨膜激活剂和钙调亲环素配体相互作用分子（TACI）、B细胞成熟抗原（BCMA）、BAFF受体（BAFF-R）结合，以调节B细胞的存活、分化和增殖。BLyS基因表达和调控所涉及的机制仍未完全明确。在本研究中，我们检测了B细胞非霍奇金淋巴瘤（NHL-B）细胞中BLyS基因的表达、功能及调控。我们的研究表明，BLyS在侵袭性NHL-B细胞中组成性表达，包括大B细胞淋巴瘤（LBCL）和套细胞淋巴瘤（MCL），在恶性B细胞的存活和增殖中发挥重要作用。我们发现，2种重要的转录因子，即核因子κB（NF-κB）和活化T细胞核因子（NFAT），通过BLyS启动子中至少1个NF-κB结合位点和2个NFAT结合位点参与调控BLyS的表达。我们还提供证据表明，NHL-B细胞中NF-κB和BLyS的组成性激活形成了一个与淋巴瘤细胞存活和增殖相关的正反馈环。我们的研究结果表明，组成性NF-κB和NFAT激活是恶性B细胞中BLyS存活通路的关键转录调节因子，可能是侵袭性NHL-B的治疗靶点。
