Yaccoby S, Pennisi A, Li X, Dillon S R, Zhan F, Barlogie B, Shaughnessy J D
Myeloma Institute for Research and Therapy, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Leukemia. 2008 Feb;22(2):406-13. doi: 10.1038/sj.leu.2405048. Epub 2007 Nov 29.
APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI(high)) versus a plasmablastic signature (TACI(low)). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI(high) but not TACI(low) myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI(high) myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI(high) bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.
增殖诱导配体（APRIL）和B淋巴细胞刺激因子/B细胞活化因子（BLyS/BAFF，肿瘤坏死因子（TNF）家族成员）已被证明是某些骨髓瘤细胞在体外的存活因子。BAFF可与肿瘤坏死因子相关受体结合，如B细胞成熟抗原（BCMA）、跨膜激活剂和CAML相互作用分子（TACI）以及BAFF受体（BAFFR），而APRIL则与TACI、BCMA以及硫酸乙酰肝素蛋白聚糖（HSPG）如Syndecan-1结合。据报道，骨髓瘤中TACI基因表达可区分具有微环境依赖性特征（TACI（高））的肿瘤与浆母细胞样特征（TACI（低））的肿瘤。我们在SCID-hu模型以及与破骨细胞共培养的条件下，测试了阿他西普（以前称为TACI-Ig，可阻断APRIL和BAFF）和BAFFR-Ig（仅阻断BAFF）对原发性骨髓瘤生长的影响。除少数例外情况外，阿他西普以及程度较轻的BAFFR-Ig在体内和体外均抑制了TACI（高）而非TACI（低）骨髓瘤样本的生长，且反应率与TACI表达呈负相关。根据我们最近描述的70基因模型，大多数TACI（高）骨髓瘤细胞在分子水平上被归类为低风险。破骨细胞高表达APRIL和BAFF，骨髓瘤细胞与破骨细胞共培养后，APRIL和BAFF表达上调。我们的研究结果表明，APRIL在TACI（高）的依赖骨髓的骨髓瘤细胞存活中起重要作用，TACI基因表达可能是预测哪些患者可从阿他西普治疗中获益的有用标志物。
