ASH2L-Promoted HOXC8 Gene Expression Plays a Role in Mixed Lineage Leukemia-Rearranged Acute Leukemia.

Autor: Wu YJ; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China., Li LX; Department of Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210011, Jiangsu Province, People's Republic of China., Liu L; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China., Zhao SS; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China., Qiu HR; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China., Wang H; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China.
Jazyk: angličtina
Zdroj: OncoTargets and therapy [Onco Targets Ther] 2020 Jan 14; Vol. 13, pp. 381-387. Date of Electronic Publication: 2020 Jan 14 (Print Publication: 2020).
DOI: 10.2147/OTT.S221643
Abstrakt: Background: Mixed lineage leukemia (MLL) fusion protein alone exhibits poor histone lysine methyltransferase (HKMT) activity in catalyzing histone H3 Lys4 trimethylation (H3K4me3) in MLL-rearranged acute leukemia.
Methods: To explore the HKMT effect of another regulatory protein within the complex of proteins associated with Set 1 (COMPASS), we analyzed the H3K4me3 modification of the HOXC8 promoter under the action of ASH2L regulation. Small interfering RNA of ASH2L, chromatin immunoprecipitation, real-time-PCR (RT-PCR), and Western blotting were used to detect the expression of specific regions of the HOXC8 promoter, RBBP5, WDR5, MLL, and BRTF in two MLL-rearranged acute leukemia cell lines (RS4:11 and THP-1 cells).
Results: The gene and protein expression levels of HOXC8 were significantly downregulated upon treatment with ASH2L-siRNA (as analyzed by targeting specific regions of the HOXC8 promoter located 0 and 3 kb (-3.0 kb) upstream of the transcriptional start site in RSH:11 cells; and -3.0 and -2.0 kb upstream of the transcriptional start site, and +1.4 kb downstream of the transcriptional start site in THP-1 cells). The expression levels of the BRTF, RBBP5, WDR5, and MLL genes were significantly downregulated from the different transcriptional start sites of the HOXC8 promoter in the RSH:11 cell line (P < 0.05). Furthermore, the BPTF and RBBP5 genes were downregulated from the HOXC8 promoter in the THP-1 cell line (P < 0.05).
Conclusion: Based on these results, we suggest a new concept of histone modification of the ASH2L protein in MLL-rearranged acute leukemia, which cannot carry out methyltransferase activity independently. The protein-protein interactions of ASH2L with other COMPASS members, such as MLL, WDR5, RBBP5, and chromatin remodeling factor BRTF, appear to be essential for its role in the activation of HOXC8 gene transcription.
Competing Interests: The authors report no conflicts of interest relating to this work.
(© 2020 Wu et al.)
Databáze: MEDLINE
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