Howard Hughes Medical Institute, Chapel Hill, NC, USA.
Blood. 2011 Jun 23;117(25):6912-22. doi: 10.1182/blood-2011-02-334359. Epub 2011 Apr 26.
Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9-induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up-regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9-mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations.
染色体易位的混合谱系白血病（MLL）基因是急性白血病的一个常见原因。MLL 融合蛋白的致癌功能部分是通过异常激活 Hoxa 基因和 Meis1 等基因介导的。在这里，我们使用他莫昔芬诱导的 Cre 介导的功能丧失小鼠模型证明，H3K79 甲基转移酶 DOT1L 是体外和体内 MLL-AF9 诱导的白血病发生所必需的，无论是起始还是维持。通过基因表达和染色质免疫沉淀分析，我们证明了 DOT1L 的靶向错误、随后的 H3K79 甲基化以及 Hoxa 和 Meis1 基因的上调是 DOT1L 如何促进 MLL-AF9 介导的白血病发生的分子机制。我们的研究不仅为 DOT1L 在白血病中的功能提供了第一个体内证据，也揭示了 DOT1L 在 MLL-AF9 介导白血病中的分子机制。因此，DOT1L 可能成为治疗由 MLL 易位引起的白血病的潜在治疗靶点。
