MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.
MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.
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DOI：
10.1016/j.celrep.2015.12.003
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发表时间：
2015-12-29
期刊：
影响因子：
8.8
通讯作者：
Konopleva M
中科院分区：
文献类型：
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作者：
Benito JM;Godfrey L;Kojima K;Hogdal L;Wunderlich M;Geng H;Marzo I;Harutyunyan KG;Golfman L;North P;Kerry J;Ballabio E;Chonghaile TN;Gonzalo O;Qiu Y;Jeremias I;Debose L;O'Brien E;Ma H;Zhou P;Jacamo R;Park E;Coombes KR;Zhang N;Thomas DA;O'Brien S;Kantarjian HM;Leverson JD;Kornblau SM;Andreeff M;Müschen M;Zweidler-McKay PA;Mulloy JC;Letai A;Milne TA;Konopleva M
旨在利用侵袭性癌症的特定分子途径的靶向治疗是当前研究的一个令人兴奋的领域。混合谱系白血病 (MLL) 突变（例如 t(4;11) 易位）会导致传统治疗难以治愈的侵袭性白血病。 t(4;11) 易位产生 MLL/AF4 融合蛋白，通过表观遗传和转录延伸机制激活关键靶基因。在这项研究中，我们发现 t(4;11) 患者细胞表达高水平的 BCL-2，并且对 BCL-2 特异性 BH3 模拟物 ABT-199 的治疗高度敏感。我们证明 MLL/AF4 通过 DOT1L 介导的 H3K79me2/3 特异性上调 BCL-2 基因，但不上调其他 BCL-2 家族成员。我们使用此信息来表明 t(4;11) 细胞系对 ABT-199 和 DOT1L 抑制剂的组合敏感。此外，ABT-199在异种移植模型中与标准诱导型疗法具有协同作用，提倡将ABT-199引入MLL重排白血病的治疗方案中。 MLLr ALL 母细胞表达高水平的 BCL-2、BAX 和 BIM MLL/AF4 通过 H3K79 甲基化激活 BCL2 MLLr ALL 细胞对 BCL-2 拮抗剂 ABT-199 极其敏感 ABT-199 治疗与 MLLr 样本上的 H3K79 甲基化抑制剂具有协同作用 旨在利用侵袭性癌症中特定分子途径的疗法是一个令人兴奋的研究领域。 MLL 基因突变会导致侵袭性、无法治愈的白血病。贝尼托等人。研究表明，MLL 白血病对 BCL-2 抑制剂高度敏感，尤其是与针对突变 MLL 复合物活性的药物联合使用时。
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias. MLLr ALL blasts express high levels of BCL-2, BAX, and BIM MLL/AF4 activates BCL2 through H3K79 methylation MLLr ALL cells are exquisitely sensitive to BCL-2 antagonist ABT-199 ABT-199 treatment synergizes with H3K79 methylation inhibitors on MLLr samples Therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of research. Mutations in the MLL gene cause aggressive incurable leukemias. Benito et al. show that MLL leukemias are highly sensitive to BCL-2 inhibitors, especially when combined with drugs that target mutant MLL complex activity.