A CRISPR/CAS9‐based strategy targets the personalized chimeric neosequence in fusion‐driven cancer genome for precision medicine

Huang, Wei; Zeng, Zhan-Cheng; Wang, Wen-Tao; Sun, Yu-Meng; Chen, Yue‐Qin; Luo, Xue-Qun; Fang, Ke

doi:10.1002/ctm2.355

Cited by 2 publications

(2 citation statements)

References 10 publications

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“…Understanding the regulation and degradation of oncogenic fusion proteins could revolutionize targeted therapy in cancers with unfavorable outcomes [ 28 – 30 , 40 , 41 ]. It has been reported that chromosomal rearrangements that involve transcriptional regulators occur in 38% of hematological malignancies and in 44% of solid tumors that have abnormal karyotypes [ 1 , 2 ].…”

Section: Discussionmentioning

confidence: 99%

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

Chen,

Huang,

Zhu

et al. 2024

Exp Hematol Oncol

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Background Mixed-lineage leukemia (MLL) fusion gene caused by chromosomal rearrangement is a dominant oncogenic driver in leukemia. Due to having diverse MLL rearrangements and complex characteristics, MLL leukemia treated by currently available strategies is frequently associated with a poor outcome. Therefore, there is an urgent need to identify novel therapeutic targets for hematological malignancies with MLL rearrangements. Methods qRT-PCR, western blot, and spearman correction analysis were used to validate the regulation of LAMP5-AS1 on LAMP5 expression. In vitro and in vivo experiments were conducted to assess the functional relevance of LAMP5-AS1 in MLL leukemia cell survival. We utilized chromatin isolation by RNA purification (ChIRP) assay, RNA pull-down assay, chromatin immunoprecipitation (ChIP), RNA fluorescence in situ hybridization (FISH), and immunofluorescence to elucidate the relationship among LAMP5-AS1, DOT1L, and the LAMP5 locus. Autophagy regulation by LAMP5-AS1 was evaluated through LC3B puncta, autolysosome observation via transmission electron microscopy (TEM), and mRFP-GFP-LC3 puncta in autophagic flux. Results The study shows the crucial role of LAMP5-AS1 in promoting MLL leukemia cell survival. LAMP5-AS1 acts as a novel autophagic suppressor, safeguarding MLL fusion proteins from autophagic degradation. Knocking down LAMP5-AS1 significantly induced apoptosis in MLL leukemia cell lines and primary cells and extended the survival of mice in vivo. Mechanistically, LAMP5-AS1 recruits the H3K79 histone methyltransferase DOT1L to LAMP5 locus, directly activating LAMP5 expression. Importantly, blockade of LAMP5-AS1-LAMP5 axis can represses MLL fusion proteins by enhancing their degradation. Conclusions The findings underscore the significance of LAMP5-AS1 in MLL leukemia progression through the regulation of the autophagy pathway. Additionally, this study unveils the novel lncRNA-DOT1L-LAMP5 axis as promising therapeutic targets for degrading MLL fusion proteins.

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Section: Discussionmentioning

confidence: 99%

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

Chen,

Huang,

Zhu

et al. 2024

Exp Hematol Oncol

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“…In recent years, CRISPR/Cas9, which is a highly specific and efficient tool to edit the genome, has also been used in circRNA knockout [ 123 , 142 ]. In general, the CRISPR/Cas9 system knocks out special circRNAs by deleting intronic complementary sequences neighboring circularized exons in circRNA biogenesis [ 5 , 46 , 143 – 145 ] (Fig.…”

Section: Characterization Of Circrnasmentioning

confidence: 99%

New insight into circRNAs: characterization, strategies, and biomedical applications

Feng,

Zhu,

et al. 2023

Exp Hematol Oncol

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Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs are derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput RNA sequencing and experimental technologies have enabled the extensive identification and characterization of circRNAs, such as novel types of biogenesis, tissue-specific and cell-specific expression patterns, epigenetic regulation, translation potential, localization and metabolism. Increasing evidence has revealed that circRNAs participate in diverse cellular processes, and their dysregulation is involved in the pathogenesis of various diseases, particularly cancer. In this review, we systematically discuss the characterization of circRNAs, databases, challenges for circRNA discovery, new insight into strategies used in circRNA studies and biomedical applications. Although recent studies have advanced the understanding of circRNAs, advanced knowledge and approaches for circRNA annotation, functional characterization and biomedical applications are continuously needed to provide new insights into circRNAs. The emergence of circRNA-based protein translation strategy will be a promising direction in the field of biomedicine.

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A CRISPR/CAS9‐based strategy targets the personalized chimeric neosequence in fusion‐driven cancer genome for precision medicine

Cited by 2 publications

References 10 publications

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

New insight into circRNAs: characterization, strategies, and biomedical applications

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