Epigenetic consequences of MLL fusion protein expression

MLL 融合蛋白表达的表观遗传后果

• 批准号: 170623019
• 负责人: Professor Dr. Robert Slany
• 金额: --
• 依托单位: Lehrstuhl für Genetik - AG Falk Nimmerjahn
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/170623019?language=en
• 关键词: Epigenetic; consequences; MLL; fusion; protein

Certain subtypes of particularly aggressive leukemia are characterized by the presence of a chromosomal translocation that affects the long arm of chromosome eleven. This molecular event creates fusion proteins composed of parts derived from the chromatin modifying protein MLL fused to a member of a complex that normally promotes transcriptional elongation. In combination these protein chimeras work as aberrant transcription factors. Besides increasing the production rate of target RNAs, MLL fusions are also able to neutralize repressive factors (Polycomb proteins). Thus MLL fusions inactivate a safety mechanism that would normally prevent the hyper-activation of target genes leading to cellular transformation and leukemia. In this application we propose to investigate the biochemical mechanisms and the associated factors to understand how MLL fusions counteract repression. In addition we would like to examine if the frequent deletion of a tumor suppressor gene in leukemia cooperates with epigenetic treatment to exacerbate MLL fusion induced transformation.

特别侵袭性白血病的某些亚型的特征是存在影响十一号染色体长臂的染色体易位。这一分子事件产生了融合蛋白，该融合蛋白由源自染色质修饰蛋白 MLL 的部分组成，该部分与通常促进转录延伸的复合物的成员融合。这些蛋白质嵌合体组合起来作为异常转录因子。除了提高目标 RNA 的生产率外，MLL 融合还能够中和抑制因子（Polycomb 蛋白）。因此，MLL 融合使一种安全机制失活，该机制通常可以防止导致细胞转化和白血病的靶基因过度激活。在此应用中，我们建议研究生化机制和相关因素，以了解 MLL 融合如何抵消抑制。此外，我们想检查白血病中抑癌基因的频繁缺失是否与表观遗传治疗相配合，从而加剧 MLL 融合诱导的转化。

项目成果

DOTting the path to doom: how acceleration of histone methylation leads to leukemia.

• DOI: 10.1016/j.ccell.2014.11.004
• 发表时间: 2014-12
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: C. Bach;R. Slany

Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes

蛋白激酶 Msk1 在物理和功能上与 KMT2A/MLL1 甲基转移酶复合物相互作用，并有助于多个靶基因的调节

• DOI: 10.1186/s13072-016-0103-3
• 发表时间: 2016
• 期刊: Epigenetics & Chromatin
• 影响因子: 3.9
• 作者: Wiersma M;Bussiere M;Halsall JA;Turan N;Slany R;Turner BM;Nightingale KP
• 通讯作者: Nightingale KP

AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia

• DOI: 10.1038/ncb3563
• 发表时间: 2017-07-01
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Zhou, Fengbiao;Liu, Yi;Mueller-Tidow, Carsten
• 通讯作者: Mueller-Tidow, Carsten

DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.

• DOI: 10.1016/j.ccr.2012.01.021
• 发表时间: 2012-04
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: S. Takáčová;R. Slany;J. Bártková;V. Stránecký;P. Doležel;P. Lužná;J. Bartek;V. Divoký