Richardson Sarah J, Matthews Christine, Catherwood Mark A, Alexander H Denis, Carey B Sean, Farrugia Joanna, Gardiner Anne, Mould Sarah, Oscier David, Copplestone J Adrian, Prentice Archibald G
Department of Haematology Level 7, Derriford Hospital, Plymouth PL6 8DH, United Kingdom.
Blood. 2006 May 1;107(9):3584-92. doi: 10.1182/blood-2005-04-1718. Epub 2005 Dec 6.
Molecular markers like IgV(H) mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70(+) CLL B cells respond in vitro more readily than ZAP-70(-) CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70(+) CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-alpha, a survival factor produced by stromal cells) compared with ZAP-70(-) cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70(+) but not ZAP-70(-) CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70(+) disease.
诸如免疫球蛋白重链可变区（IgV(H)）突变状态、染色体异常以及CD38和ζ链相关蛋白激酶70（ZAP-70）表达等分子标志物在B细胞慢性淋巴细胞白血病（B-CLL）中具有预后价值。这些标志物可能具有致病作用，因为ZAP-70的共表达以及B细胞受体（BCR）信号传导增加，还有CD38在慢性淋巴细胞白血病中的信号传导功能。本研究表明，ZAP-70阳性的慢性淋巴细胞白血病B细胞在体外比ZAP-70阴性的慢性淋巴细胞白血病细胞和正常B细胞对趋化因子迁移信号反应更迅速，这是通过增强表面CCR7表达实现的（P = 0.009；P < 0.001），并且对其配体CCL19和CCL21的反应性增加，这通过F-肌动蛋白聚合（P < 0.05）和细胞迁移（P < 0.01）得以证明。此外，与ZAP-70阴性细胞相比，ZAP-70阳性的慢性淋巴细胞白血病细胞在用基质细胞产生的生存因子CXCL12（基质细胞衍生因子1α）刺激后表现出持续的细胞外信号调节激酶（ERK）磷酸化/激活（P = 0.004）。与护士样细胞共培养后，添加CXCL12可显著提高ZAP-70阳性而非ZAP-70阴性慢性淋巴细胞白血病细胞的存活率（P < 0.05），MEK抑制剂PD98059可部分阻断这一效应。这些有利的迁移和生存反应可能促进在假生发中心更容易进入并实现更大程度的增殖，部分解释了ZAP-70阳性疾病更具进展性的本质。
