Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.
Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.
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DOI：
10.1002/ctm2.933
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发表时间：
2022-06
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
改善婴儿白血病的不良预后仍然是一个未满足的临床需求。这种疾病是一种典型的融合癌蛋白驱动的儿科癌症，在大多数病例中存在MLL （KMT2A）融合。直接靶向这些驱动癌蛋白代表了一个独特的治疗机会。这一理论基础使我们启动了一项药物筛选，目的是发现能够阻断MLL融合癌蛋白的药物。开发了一种抑制MLL融合蛋白的筛选方法，克服了靶向转录因子的传统局限性。这种基于荧光素酶报告基因的筛选，连同二次western blot筛选，被用来对化合物进行优先排序。我们对先导化合物二硫仑（DSF）进行了表征，基于其对MLL融合蛋白的有效消融。通过细胞增殖、集落形成、细胞凋亡、RT - qPCR、体内实验、RNA - seq、ChIP - qPCR和ChIP - seq分析证实了药物诱导的MLL -融合抑制的结果。所有统计检验均为双侧检验。DSF对MLL融合蛋白的药物诱导抑制可在体外阻断MLL重排细胞的集落形成，诱导分化并阻碍体内白血病的进展。从机制上讲，DSF消除了MLL融合蛋白与DNA的结合，导致表观遗传变化和MLL融合蛋白设置的白血病程序的下调。DSF可以直接抑制MLL -融合蛋白，并在体外和体内均显示出抗肿瘤活性，据我们所知，这为直接靶向起始致癌MLL -融合蛋白的治疗提供了第一个证据。直接抑制MLL融合蛋白是一种潜在的治疗策略。MLL融合耗尽筛选发现，双硫仑具有消融MLL融合蛋白和阻断相关白血病表型的能力。Disulfiram直接靶向CXXC结构域，这是所有MLL融合蛋白所必需的。双硫仑阻止与MLL -融合靶基因的结合，导致H3K27ac水平迅速下降。
Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein‐driven paediatric cancer, with MLL (KMT2A)‐fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL‐fusion oncoproteins. A screen for inhibition of MLL‐fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter‐based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, disulfiram (DSF), based on its efficient ablation of MLL‐fusion proteins. The consequences of drug‐induced MLL‐fusion inhibition were confirmed by cell proliferation, colony formation, apoptosis assays, RT‐qPCR, in vivo assays, RNA‐seq and ChIP‐qPCR and ChIP‐seq analysis. All statistical tests were two‐sided. Drug‐induced inhibition of MLL‐fusion proteins by DSF resulted in a specific block of colony formation in MLL‐rearranged cells in vitro, induced differentiation and impeded leukaemia progression in vivo. Mechanistically, DSF abrogates MLL‐fusion protein binding to DNA, resulting in epigenetic changes and down‐regulation of leukaemic programmes setup by the MLL‐fusion protein. DSF can directly inhibit MLL‐fusion proteins and demonstrate antitumour activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly targets the initiating oncogenic MLL‐fusion protein. Direct inhibition of MLL‐fusion proteins is a potential therapeutic strategy. MLL‐fusion depletion screen identified disulfiram for its ability to ablate MLL‐fusion protein and block‐associated leukaemic phenotype. Disulfiram directly targets the CXXC domain that is essential for all MLL‐fusion proteins. Disulfiram prevents the binding to the target genes of the MLL‐fusion resulting in rapid decrease in H3K27ac levels.
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影响因子：
28.2
作者：
Gough SM;Lee F;Yang F;Walker RL;Zhu YJ;Pineda M;Onozawa M;Chung YJ;Bilke S;Wagner EK;Denu JM;Ning Y;Xu B;Wang GG;Meltzer PS;Aplan PD
通讯作者：
Aplan PD
影响因子：
2.7
作者：
Georgiou, Georgios;van Heeringen, Simon J.
通讯作者：
van Heeringen, Simon J.
DOI：
10.1007/bf01877380
发表时间：
1993-01-01
期刊：
BIOTHERAPY
影响因子：
--
作者：
DUFOUR, P;LANG, JM;OBERLING, F
通讯作者：
OBERLING, F
影响因子：
6.4
作者：
Buss, Eike C.;Ho, Anthony D.
通讯作者：
Ho, Anthony D.
影响因子：
64.8
作者：
Agathocleous M;Meacham CE;Burgess RJ;Piskounova E;Zhao Z;Crane GM;Cowin BL;Bruner E;Murphy MM;Chen W;Spangrude GJ;Hu Z;DeBerardinis RJ;Morrison SJ
通讯作者：
Morrison SJ