Methylation-associated silencing of BASP1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia.

Abstract

The AML1-ETO fusion protein (A/E), which results from the t(8;21) translocation, is considered to be a leukemia-initiating event. Identifying the mechanisms underlying the oncogenic activity of A/E remains a major challenge. In this study, we identified a specific down-regulation of brain acid-soluble protein 1 (BASP1) in t(8;21) acute myeloid leukemia (AML). A/E recognized AML1-binding sites and recruited DNA methyltransferase 3a (DNMT3a) to the BASP1 promoter sequence, which triggered DNA methylation-mediated silencing of BASP1. Ectopic expression of BASP1 inhibited proliferation and the colony-forming ability of A/E-positive AML cell lines and led to apoptosis and cell cycle arrest. The DNMT inhibitor decitabine up-regulated the expression of BASP1 in A/E-positive AML cell lines. In conclusion, our data suggest that BASP1 silencing via promoter methylation may be involved in A/E-mediated leukemogenesis and that BASP1 targeting may be an actionable therapeutic strategy in t(8;21) AML.

• Authors: Lei Zhou, Lin Fu, Na Lv, Jing Liu, Yan Li, Xiaosu Chen, Qingyu Xu, Guofeng Chen, Baoxu Pang, Lili Wang, Yonghui Li, Xiaodong Zhang, Li Yu
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 50 Issue 4 Pg. 1-8 (04 20 2018) ISSN: 2092-6413 [Electronic] United States
• PMID: 29674693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AML1-ETO fusion protein, human
• BASP1 protein, human
• Core Binding Factor Alpha 2 Subunit
• DNMT3A protein, human
• Membrane Proteins
• Nerve Tissue Proteins
• Oncogene Proteins, Fusion
• RUNX1 Translocation Partner 1 Protein
• Repressor Proteins
• DNA Methyltransferase 3A

Topics

• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Chromosomes, Human, Pair 21 (genetics, metabolism)
• Chromosomes, Human, Pair 8 (genetics, metabolism)
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• DNA Methylation
• DNA Methyltransferase 3A
• Gene Silencing
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism, pathology)
• Membrane Proteins (biosynthesis, genetics)
• Nerve Tissue Proteins (biosynthesis, genetics)
• Oncogene Proteins, Fusion (genetics, metabolism)
• RUNX1 Translocation Partner 1 Protein (genetics, metabolism)
• Repressor Proteins (biosynthesis, genetics)
• THP-1 Cells
• Translocation, Genetic
• U937 Cells