直接功能性HOXA9/ dna结合竞争者与HOXA9表达的表观遗传抑制剂对mll重排急性髓系白血病模型中细胞增殖、死亡和分化过程的影响

IF 2.7 3区 医学 Q2 ONCOLOGY
Julie Vrevin, Mélanie Lambert, Marine Andrique, Nathalie Jouy, Marie-Hélène David-Cordonnier
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引用次数: 0

摘要

癌症治疗的最新进展导致了针对特定致癌驱动因素的先进治疗方法的发展,例如,新的小分子靶向药物,抗体-药物偶联物,肽药物,细胞或基因治疗。关键靶点可能是突变/融合蛋白本身,也可能是表达直接失调并参与增殖、抵抗细胞死亡或其他与致癌过程相关的细胞过程的蛋白。确定最佳治疗策略需要评估改变蛋白的抑制剂和与病理相关的失调癌基因。在此背景下,急性髓性白血病(AML)的mll重排亚型(MLL-r)由于预后不良、频繁复发和治疗耐药而面临重大挑战。已知MLL-r AMLs依赖于癌基因转录因子HOXA9,其分化阻断依赖于其结合DNA的能力。近年来,一些MLL-r表观遗传复合物抑制剂已被开发出来,其中一些已进入临床试验。我们鉴定并优化了两种HOXA9功能抑制剂DB818和DB1055,它们在dna结合水平上起作用。本研究比较了间接(表观遗传MLL抑制剂)和直接(DNA结合)HOXA9抑制剂在两种不同的儿童MLL-r细胞模型THP-1和MV4-11中的细胞效应。我们的研究结果表明,DB818和DB1055对HOXA9的直接dna结合抑制在促进白血病细胞分化、损害不受控制的增殖和促进细胞死亡方面具有更有利的结果。因此,对成瘾癌基因HOXA9的直接dna结合抑制可能为MLL-r治疗提供了一个有趣的机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia.

Recent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule-targeted agents, antibody-drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy.

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来源期刊
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
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