Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Leukemia. 2012 Apr;26(4):682-92. doi: 10.1038/leu.2011.278. Epub 2011 Oct 21.
MLL-rearranged infant acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by a unique gene-expression profile. We uncovered that the activation of particular (proto-onco)genes is mediated by promoter hypomethylation. In search for therapeutic agents capable of targeting these potential cancer-promoting genes, we applied connectivity mapping on a gene expression signature based on the genes most significantly hypomethylated in t(4;11)-positive infant ALL as compared with healthy bone marrows. This analysis revealed histone deacetylase (HDAC) inhibitors as suitable candidates to reverse the unfavorable gene signature. We show that HDAC inhibitors effectively induce leukemic cell death in t(4;11)-positive primary infant ALL cells, accompanied by downregulation of MYC, SET, RUNX1, RAN as well as the MLL-AF4 fusion product. Furthermore, DNA methylation was restored after HDAC inhibitor exposure. Our data underlines the essential role for epigenetic de-regulation in MLL-rearranged ALL. Furthermore, we show, for the first time, that connectivity mapping can indirectly be applied on DNA methylation patterns, providing a rationale for HDAC inhibition in t(4;11)-positive leukemias. Given the presented potential of HDAC inhibitors to target important proto-oncogenes including the leukemia-specific MLL fusion in vitro, these agents should urgently be tested in in vivo models and subsequent clinical trials.
MLL 重排婴儿急性淋巴细胞白血病 (ALL) 是一种侵袭性白血病，其特征是具有独特的基因表达谱。我们发现，特定（原癌）基因的激活是由启动子低甲基化介导的。为了寻找能够靶向这些潜在致癌基因的治疗药物，我们在基于 t(4;11)阳性婴儿 ALL 中与健康骨髓相比甲基化程度最低的基因的基因表达特征上应用了连接性映射。这项分析表明组蛋白去乙酰化酶 (HDAC) 抑制剂是逆转不良基因特征的合适候选药物。我们表明，HDAC 抑制剂可有效诱导 t(4;11)阳性原代婴儿 ALL 细胞中的白血病细胞死亡，同时下调 MYC、SET、RUNX1、RAN 以及 MLL-AF4 融合产物。此外，在 HDAC 抑制剂暴露后，DNA 甲基化得到了恢复。我们的数据强调了表观遗传失调在 MLL 重排 ALL 中的重要作用。此外，我们首次表明，连接性映射可以间接应用于 DNA 甲基化模式，为 t(4;11)阳性白血病中的 HDAC 抑制提供了依据。鉴于 HDAC 抑制剂在体外靶向包括白血病特异性 MLL 融合在内的重要原癌基因的潜力，这些药物应紧急在体内模型和随后的临床试验中进行测试。
