Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.
Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.
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DOI：
10.1158/2159-8290.cd-13-0117
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发表时间：
2013-09
期刊：
影响因子：
28.2
通讯作者：
Cerchietti L
中科院分区：
文献类型：
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作者：
Clozel T;Yang S;Elstrom RL;Tam W;Martin P;Kormaksson M;Banerjee S;Vasanthakumar A;Culjkovic B;Scott DW;Wyman S;Leser M;Shaknovich R;Chadburn A;Tabbo F;Godley LA;Gascoyne RD;Borden KL;Inghirami G;Leonard JP;Melnick A;Cerchietti L
尽管异常 DNA 甲基化模式是癌症的一个标志，但针对大多数肿瘤的靶向 DNA 甲基转移酶 (DNMT) 的相关性仍不清楚。在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中，我们观察到化疗耐药性与异常的 DNA 甲基化编程相关。长期暴露于低剂量 DNMT 抑制剂 (DNMTIs) 可使化疗耐药细胞重新编程，使其对阿霉素敏感，且体内无重大毒性。在化疗耐药的 DLBCL 中，有 9 个基因反复出现高甲基化。其中，SMAD1 是一个关键贡献者，化疗增敏需要重新激活。一项 I 期临床研究评估了新诊断的高危 DLBCL 患者中阿扎胞苷启动后标准化学免疫疗法的效果。该组合具有良好的耐受性，并且完全缓解率很高。阿扎胞苷治疗前后的活检证实了 SMAD1 去甲基化和化疗增敏，描绘了 DNMTIs 临床使用的个性化策略。
Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. The combination was well tolerated and yielded a high rate of complete remission. Pre and post azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.