Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk
Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk
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DOI：
10.1038/sj.leu.2404437
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发表时间：
2006-12-01
期刊：
影响因子：
11.4
通讯作者：
Ball, E. D.
中科院分区：
文献类型：
--
作者：
Balaian, L.;Ball, E. D.
急性髓系白血病 (AML) 细胞表达细胞表面抗原 CD33，与单克隆抗体 (mAb) 连接后，CD33 会以 Syk 依赖性方式下调细胞生长。与毒素 gemtuzumab ozogamicin (GO) 偶联的抗 CD33 mAb 用于治疗 AML (Mylotarg)。因此，我们研究了 AML 细胞对 GO 治疗的反应是否也依赖于 Syk 表达。测试了 40 个原发性 AML 样本（25 个 Syk 阳性和 15 个 Syk 阴性）对 GO 和未修饰的抗 CD33 mAb 的抗增殖作用的反应。发现 Syk 表达与白血病细胞对 GO 和抗 CD33 mAb 的反应之间存在相关性。小干扰 RNA 对 Syk 的“阻断”导致 AML 细胞对 GO 和抗 CD33 mAb 介导的细胞毒性均无反应。在某些情况下，去甲基化剂 5-氮杂胞苷 (5-aza) 上调 Syk 会诱导 Syk 重新表达，从而增强 GO 和抗 CD33 介导的对白血病细胞生长的抑制作用。因此，原发性 AML 样本中 GO 和抗 CD33 的细胞毒性与 Syk 表达相关。 5-Aza 恢复了 Syk，并将最初 Syk 阴性、对 CD33 连接无反应的细胞的敏感性提高到 Syk 阳性细胞的水平。这些数据对于预测 GO 反应和设计临床试验具有临床意义。
Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that, upon ligation with a monoclonal antibody (mAb), is a downregulator of cell growth in a Syk-dependent manner. An anti-CD33 mAb coupled to a toxin, gemtuzumab ozogamicin (GO), is used for the treatment of AML (Mylotarg). Therefore, we investigated whether the response of AML cells to GO treatment also depends on Syk expression. Forty primary AML samples (25 Syk-positive and 15 Syk-negative) were tested for their response to the anti-proliferative effects of GO and unmodified anti-CD33 mAb. A correlation between Syk expression and the response of leukemia cells to GO and anti-CD33 mAb was found. 'Blocking' of Syk by small interfering RNA resulted in unresponsiveness of AML cells to both GO and anti-CD33 mAb-mediated cytotoxicity. Syk upregulation by the demethylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, resulting in enhanced GO and anti-CD33 mediated inhibition of leukemia cell growth. Thus, the cytotoxicity of both GO and anti-CD33 in primary AML samples was associated with Syk expression. 5-Aza restored Syk and increased the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. These data have clinical significance for predicting response to GO and designing clinical trials.