MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
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ABSTRACT:
SUBMITTER: Bernt KM
PROVIDER: S-EPMC3329803 | biostudies-literature | 2011 Jul
REPOSITORIES: biostudies-literature
Publications
MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
Bernt Kathrin M KM Bernt Kathrin M KM Zhu Nan N Sinha Amit U AU Vempati Sridhar S Faber Joerg J Krivtsov Andrei V AV Feng Zhaohui Z Punt Natalie N Daigle Amanda A Bullinger Lars L Pollock Roy M RM Richon Victoria M VM Kung Andrew L AL Armstrong Scott A SA
Cancer cell 20110701 1
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downre ...[more]
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| S-EPMC6788006 | biostudies-literature
Project description:Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein-protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.
| S-EPMC8944089 | biostudies-literature