A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias.
A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias.
复制标题
DOI：
10.1158/0008-5472.can-10-0300
复制
发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Heisterkamp N
中科院分区：
文献类型：
--
作者：
Parameswaran R;Müschen M;Kim YM;Groffen J;Heisterkamp N
b系急性淋巴细胞白血病（ALL）是由祖细胞（前b细胞）的转化引起的。成人的治愈率仍然很低，微环境对白血病细胞的支持使治疗变得复杂，这表明迫切需要更好地了解促进白血病细胞存活的因素。B细胞活化因子（BAFF）及其受体BAFF- r对成熟正常和恶性B细胞的存活和生长具有重要作用，但在B前细胞中不表达。出乎意料的是，在原发性philadelphia -染色体阳性和阴性all样本中，所有细胞表面的BAFF-R高表达都呈阳性。BAFF- r完全能够结合BAFF，受体的刺激激活了经典和非典型的NFκB通路。重组BAFF支持无基质的ALL细胞存活，并显著降低尼罗替尼（一种用于治疗费城染色体阳性ALL细胞的药物）引起的细胞凋亡率。令人惊讶的是，BAFF mRNA和蛋白也在相同的细胞中表达，但BAFF没有脱落到培养基中。我们的报告首次显示BAFF-R在b前ALL细胞中普遍表达，并开启了阻断其功能作为辅助治疗策略的可能性。
B-lineage acute lymphoblastic leukemia (ALL) arises by transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival. B cell activating factor (BAFF) and its receptor BAFF-R are important for survival and growth of mature normal and malignant B-cells but are not expressed on pre-B cells. Unexpectedly, all cells in the primary Philadelphia-chromosome positive and negative ALL samples tested were positive for high BAFF-R cell surface expression. The BAFF-R was fully competent to bind BAFF and stimulation of the receptor activated both the classical and the non-canonical NFκB pathways. Recombinant BAFF supported survival of the ALL cells in the absence of stroma, and it significantly attenuated the rate of apoptosis caused by exposure to nilotinib, a drug used therapeutically to treat Philadelphia-chromosome positive ALLs. Surprisingly, BAFF mRNA and protein were also expressed in the same cells but BAFF was not shed into the medium. Our report is the first showing universal expression of the BAFF-R by pre-B ALL cells and opens the possibility of blocking its function as an adjuvant therapeutic strategy.