Sevdali Eirini, Katsantoni Eleni, Smulski Cristian R, Moschovi Maria, Palassopoulou Maria, Kolokotsa Eleni-Nefeli, Argentou Nikoletta, Giannakoulas Nikolaos, Adamaki Maria, Vassilopoulos Georgios, Polychronopoulou Sophia, Germenis Anastasios E, Eibel Hermann, Speletas Matthaios
Department of Immunology and Histocompatibility, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Basic Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Front Oncol. 2019 Jul 18;9:594. doi: 10.3389/fonc.2019.00594. eCollection 2019.
BAFF, APRIL and their receptors regulate the survival, maturation and homeostasis of mature B-cells. Despite the lack of a functional role of BAFF/APRIL system during normal early B-cell development, previous studies indicated a contribution of these molecules in the pathogenesis of B-lineage acute lymphoblastic leukemia (B-ALL). Here, we evaluated the expression of this system in B-ALL and its involvement in spontaneous and drug-induced apoptosis of B-lymphoblasts, taking into consideration the distinct disease subtypes. We found that BAFFR is the most predominant aberrantly expressed receptor in B-ALL and that its expression, along with BCMA and APRIL, positively correlates with the maturation stage of B-lymphoblasts. Moreover, the binding of the E2A-PBX1 chimeric protein to the promoter suggests that the transcriptional activator promotes the increase in expression observed in about 50% of pre-B-ALL patients carrying the translocation. BAFF binding to BAFFR led to the processing of NF-κB2 p100 in pre-B ALL cells suggesting that BAFFR can activate the NF-κB2 pathway in pre-B ALL cells. Surprisingly, we found that BAFF treatment promotes the cell death of primary BCR-ABL BAFFR pre-B-lymphoblasts in adult B-ALL. It also enhances glucocorticoid-induced apoptosis in the E2A-PBX1 pre-B-ALL cell line 697. These data suggest that BAFF/BAFFR signaling in B-ALL cells differs from normal B cells and that it may affect the pathogenesis of the disease.
B细胞活化因子（BAFF）、增殖诱导配体（APRIL）及其受体调节成熟B细胞的存活、成熟和内环境稳定。尽管BAFF/APRIL系统在正常早期B细胞发育过程中缺乏功能性作用，但先前的研究表明这些分子在B系急性淋巴细胞白血病（B-ALL）的发病机制中发挥作用。在此，我们评估了该系统在B-ALL中的表达及其在B淋巴母细胞自发凋亡和药物诱导凋亡中的作用，并考虑了不同的疾病亚型。我们发现BAFF受体（BAFFR）是B-ALL中最主要的异常表达受体，其表达与B细胞成熟抗原（BCMA）和APRIL的表达一起与B淋巴母细胞的成熟阶段呈正相关。此外，E2A-PBX1嵌合蛋白与启动子的结合表明，转录激活因子促进了约50%携带该易位的前B-ALL患者中观察到的BAFFR表达增加。BAFF与BAFFR的结合导致前B-ALL细胞中NF-κB2 p100的加工，提示BAFFR可激活前B-ALL细胞中的NF-κB2通路。令人惊讶的是，我们发现BAFF处理可促进成人B-ALL中原发性BCR-ABL BAFFR前B淋巴母细胞的细胞死亡。它还增强了E2A-PBX1前B-ALL细胞系697中糖皮质激素诱导的凋亡。这些数据表明，B-ALL细胞中的BAFF/BAFFR信号传导与正常B细胞不同，可能影响该疾病的发病机制。
