Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia
Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia
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DOI：
10.1002/ajh.22141
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发表时间：
2011-11-01
影响因子：
12.8
通讯作者：
Kroeger, Nicolaus
中科院分区：
文献类型：
--
作者：
Atanackovic, Djordje;Luetkens, Tim;Kroeger, Nicolaus
肿瘤-睾丸抗原（CTA）是肿瘤免疫治疗的重要靶点。然而，CTA在急性髓细胞白血病（AML）中表达的广泛情况尚不清楚。CTA的表达进行了分析，在正常骨髓（BM），以及在AML细胞系治疗前和治疗后与去甲基化剂和/或组蛋白乙酰化酶抑制剂。然后在去甲基化治疗前后的AML患者样本中确定具有严格肿瘤限制表达的选定CTA的存在。筛选AML细胞系中20种CTA的表达，我们鉴定了AML限制性表达的6种基因（MAGE-A3、PRAME、ROPN 1、SCP-1、SLLP 1和SPO 11）。分析这些CTA在AML患者（N = 5 64）的原始细胞样本中的表达，我们发现所有样本均为MAGE-A3和SPO 11阴性，而少数患者表达ROPN 1（1.6%），SCP-1（3.1%）或SLLP 1（9.4%）。大部分患者（53.1%）表达的唯一CTA是PRAME。在用5 '-氮杂-2'-脱氧胞苷进行去甲基化处理后，我们观察到AML细胞系中CTA，特别是SSX-2的表达增加或从头表达。在AML患者中，我们检测到5-氮杂胞苷脱甲基治疗后PRAME表达增加和SSX-2诱导。除PRAME外，CTA大多不存在于AML原始细胞中。然而，去甲基化处理诱导CTA的强表达，特别是SSX-2，在体外和体内。因此，我们建议AML的CTA特异性免疫疗法应优先靶向PRAME和/或应与去甲基化剂的应用相结合，为CTA SSX-2等替代靶点开辟前景。Am.血液学杂志86：918-922，2011. (C)2011 Wiley-Liss，Inc.
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 = 5 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. Am. J. Hematol. 86: 918-922, 2011. (C) 2011 Wiley-Liss, Inc.