Kern Catherine, Cornuel Jean-Francois, Billard Christian, Tang Ruoping, Rouillard Danielle, Stenou Virginie, Defrance Thierry, Ajchenbaum-Cymbalista Florence, Simonin Pierre-Yves, Feldblum Sophie, Kolb Jean-Pierre
U365 INSERM, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Blood. 2004 Jan 15;103(2):679-88. doi: 10.1182/blood-2003-02-0540. Epub 2003 Sep 22.
Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-kappaB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.
肿瘤坏死因子（TNF）超家族成员BAFF（即TNF家族的B细胞活化因子）和增殖诱导配体APRIL参与正常B细胞的存活和分化。它们与3种受体相互作用：BAFF特有的BAFF-R，以及BAFF和APRIL共有的TACI和BCMA。我们测试了这些蛋白在B细胞慢性淋巴细胞白血病（B-CLL）抗凋亡中的潜在作用。在白血病B细胞中发现了TACI和BAFF-R的mRNA。在B-CLL白血病细胞以及正常血液或扁桃体来源的B淋巴细胞中检测到了BAFF和APRIL的mRNA及蛋白。然而，与正常B淋巴细胞不同，BAFF和APRIL在白血病细胞膜上表达。添加可溶性BAFF或APRIL可保护B-CLL细胞免受自发和药物诱导的凋亡，并刺激NF-κB活化。相反，添加可溶性BCMA-Fc或抗BAFF和抗APRIL抗体可增强B-CLL细胞凋亡。此外，使用表面增强激光解吸/电离飞行时间质谱（SELDI-TOF MS）在B-CLL患者血清中检测到了可溶性BAFF形式，但在健康供体血清中未检测到。综上所述，我们的结果表明，B-CLL细胞可通过涉及BAFF、APRIL及其受体的自分泌过程从凋亡中获救。抑制BAFF和APRIL途径可能对B-CLL治疗具有治疗价值。
