Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia
Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia
复制标题
DOI：
10.1182/blood-2002-06-1683
复制
发表时间：
2002-12-15
期刊：
影响因子：
20.3
通讯作者：
Kipps, TJ
中科院分区：
文献类型：
--
作者：
Chen, LG;Widhopf, G;Kipps, TJ
我们检测了慢性淋巴细胞白血病（CLL）患者分离的白血病B细胞中ζ相关蛋白70 （ZAP-70）的表达。具有非突变免疫球蛋白可变区基因（V基因）的CLL B细胞表达的ZAP-70蛋白水平与正常血液T细胞表达的水平相当。相比之下，具有突变的免疫球蛋白可变V基因或低水平表达CD38的CLL B细胞通常不表达可检测量的ZAP-70蛋白。来自患有CLL的同卵双胞胎的白血病细胞发现ZAP-70的表达不一致，这表明b细胞ZAP-70的表达不是遗传预先决定的。与不表达ZAP-70的CLL细胞相比，将b细胞受体（BCR）复合物连接在表达ZAP-70的CLL细胞上，可诱导胞浆蛋白（包括p72(Syk)）的酪氨酸磷酸化显著增加。此外，在特殊情况下，表达突变的免疫球蛋白V基因和ZAP-70的CLL细胞在BCR连接后也经历了更高水平的酪氨酸磷酸化。在BCR结扎后，ZAP-70经历酪氨酸磷酸化，并与表面免疫球蛋白和CD79b相关，这表明ZAP-70参与BCR信号传导。这些数据表明，ZAP-70的表达与通过BCR复合物增强的信号转导有关，这可能有助于与表达非突变免疫球蛋白受体的CLL细胞相关的更具侵袭性的临床过程。
We examined isolated leukemia B cells of patients with chronic lymphocytic leukemia (CLL) for expression of zeta-associated protein 70 (ZAP-70). CLL B cells that have nonmutated immunoglobulin variable region genes (V genes) expressed levels of ZAP-70 protein that were comparable to those expressed by normal blood T cells. In contrast, CLL B cells that had mutated immunoglobulin variable V genes, or that had low-level expression of CD38, generally did not express detectable amounts of ZAP-70 protein. Leukemia cells from identical twins with CLL were found discordant for expression of ZAP-70, suggesting that B-cell expression of ZAP-70 is not genetically predetermined. Ligation of the B-cell receptor (BCR) complex on CLL cells that expressed ZAP-70 induced significantly greater tyrosine phosphorylation of cytosolic proteins, including p72(Syk), than did similar stimulation of CLL cells that did not express ZAP-70. Also, exceptional cases of CLL cells that expressed mutated immunoglobulin V genes and ZAP-70 also experienced higher levels tyrosine phosphorylation of such cytosolic proteins following BCR ligation. Following BCR ligation, ZAP-70 underwent tyrosine phosphorylation and became associated with surface immunoglobulin and CD79b, arguing for the involvement of ZAP-70 in BCR signaling. These data indicate that expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors.