Division of Hematology/Oncology, Children's Hospital, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
Leukemia. 2013 Apr;27(4):813-22. doi: 10.1038/leu.2012.327. Epub 2012 Nov 9.
The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)-AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)-AF10 fusion oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL-AF10 and CALM-AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. The treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation.
t(10;11)(p12;q23)易位和 t(10;11)(p12;q14)易位分别编码混合谱系白血病（MLL）-AF10 和克拉琳装配淋巴髓样白血病（CALM）-AF10 融合癌蛋白，这两种易位是在急性髓系白血病和急性淋巴细胞白血病患者中观察到的两种常见的染色体重排。在这里，我们通过遗传和药理学方法在小鼠模型中证明了 MLL-AF10 和 CALM-AF10 介导的转化依赖于 H3K79 甲基转移酶 Dot1l。使用条件性敲除小鼠模型靶向敲除 Dot1l 可消除体外转化的小鼠骨髓细胞以及 MLL-AF10 或 CALM-AF10 白血病的体内起始和维持。用特异性小分子抑制剂 EPZ004777 处理 MLL-AF10 和 CALM-AF10 转化细胞可抑制白血病基因如 Hoxa 基因簇和 Meis1 的表达，并选择性地损害 MLL-AF10 和 CALM-AF10 转化细胞的增殖。EPZ004777 的预处理可显著降低 MLL-AF10 或 CALM-AF10 转化骨髓细胞在体内的脾集落形成能力。这些结果表明，携带涉及 AF10 基因的染色体易位的白血病患者可能受益于抑制 H3K79 甲基化的小分子治疗药物。
