Center of Oncology, Department of Internal Medicine II, Oncology/Hematology/Stem Cell Transplantation, University Cancer Center Hamburg, Germany.
Am J Hematol. 2011 Nov;86(11):918-22. doi: 10.1002/ajh.22141. Epub 2011 Sep 2.
Cancer-testis antigens (CTA) represent attractive targets for tumor immunotherapy. However, a broad picture of CTA expression in acute myeloid leukemia (AML) is missing. CTA expression was analyzed in normal bone marrow (BM) as well as in AML cell lines before and after treatment with demethylating agents and/or histone acetylase inhibitors. Presence of selected CTA with a strictly tumor-restricted expression was then determined in samples of patients with AML before and after demethylating therapy. Screening AML cell lines for the expression of 20 CTA, we identified six genes (MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and SPO11) with an AML-restricted expression. Analyzing the expression of these CTA in blast-containing samples from AML patients (N = 64), we found all samples to be negative for MAGE-A3 and SPO11 while a minority of patients expressed ROPN1 (1.6%), SCP-1 (3.1%), or SLLP1 (9.4%). The only CTA expressed in substantial proportion of patients (53.1%) was PRAME. Following demethylating treatment with 5'-aza-2'-deoxycytidine, we observed an increased or de novo expression of CTA, in particular of SSX-2, in AML cell lines. In AML patients, we detected increased expression of PRAME and induction of SSX-2 after demethylating therapy with 5-azacytidine. With the exception of PRAME, CTA are mostly absent from AML blasts. However, demethylating treatment induces strong expression of CTA, particularly of SSX-2, in vitro and in vivo. Therefore, we propose that CTA-specific immunotherapy for AML should preferentially target PRAME and/or should be combined with the application of demethylating agents opening the perspective for alternative targets like CTA SSX-2.
癌症睾丸抗原 (CTA) 是肿瘤免疫治疗的有吸引力的靶标。然而，急性髓细胞白血病 (AML) 中 CTA 表达的全貌尚不清楚。分析了正常骨髓 (BM) 以及在用去甲基化剂和/或组蛋白乙酰化酶抑制剂处理前后 AML 细胞系中的 CTA 表达。然后，在接受去甲基化治疗前后，在 AML 患者的样本中确定了具有严格肿瘤特异性表达的选定 CTA 的存在。通过筛选 20 个 CTA 在 AML 细胞系中的表达，我们确定了 6 个基因（MAGE-A3、PRAME、ROPN1、SCP-1、SLLP1 和 SPO11）具有 AML 特异性表达。分析来自 AML 患者的含母细胞样本中这些 CTA 的表达（N=64），我们发现所有样本均为 MAGE-A3 和 SPO11 阴性，而少数患者表达 ROPN1（1.6%）、SCP-1（3.1%）或 SLLP1（9.4%）。唯一在相当一部分患者（53.1%）中表达的 CTA 是 PRAME。在用 5'-氮杂-2'-脱氧胞苷进行去甲基化治疗后，我们观察到 AML 细胞系中 CTA，特别是 SSX-2 的表达增加或新表达。在 AML 患者中，在用 5-氮杂胞苷进行去甲基化治疗后，我们检测到 PRAME 的表达增加和 SSX-2 的诱导。除了 PRAME 之外，CTA 在 AML 母细胞中大多不存在。然而，去甲基化治疗在体外和体内强烈诱导 CTA，特别是 SSX-2 的表达。因此，我们建议 AML 的 CTA 特异性免疫治疗应优先靶向 PRAME，和/或应与去甲基化剂的应用相结合，为 CTA SSX-2 等替代靶标开辟前景。
