Epigenetic silencing of UBXN8 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

The formation of the RUNX1-RUNX1T1 fusion protein, resulting from the t(8;21) translocation, is considered to be one of the initiating events of t(8;21) acute myeloid leukemia (AML). However, the mechanisms of the oncogenic mechanism of RUNX1-RUNX1T1 remain unclear. In this study, we found that RUNX1-RUNX1T1 triggers the heterochromatic silencing of UBXN8 by recognizing the RUNX1-binding sites and recruiting chromatin-remodeling enzymes to the UBXN8 promoter region. Decitabine, a specific inhibitor of DNA methylation, upregulated the expression of UBXN8 in RUNX1-RUNX1T1(+) AML cell lines. Overexpression of UBXN8 inhibited the proliferation and colony-forming ability of and promoted cell cycle arrest in t(8;21) AML cell lines. Enhancing UBXN8 levels can significantly inhibit tumor proliferation and promote the differentiation of RUNX1-RUNX1T1(+) cells in vivo. In conclusion, our results indicated that epigenetic silencing of UBXN8 via methylation of its promoter region mediated by the RUNX1-RUNX1T1 fusion protein contributes to the leukemogenesis of t(8;21) AML and that UBXN8 targeting may be a potential therapeutic strategy for t(8;21) AML. Cancer: Gene modifications promote leukemia progression The protein byproduct of a common chromosomal rearrangement in acute myeloid leukemia (AML) promotes cancerous growth by inhibiting a tumor suppressor protein. AML cells that exhibit an abnormal coupling of segments from chromosomes 8 and 21 produce a fusion protein known as RUNX1-RUNX1T1. Erna Yang of Shenzhen University General Hospital, China, and colleagues have identified a mechanism by which this protein promotes AML progression. Experiments with AML cell lines showed that RUNX1-RUNX1T1 recruits DNA-binding proteins that introduce numerous chemical modifications to the UBXN8 gene, which inhibit production of the tumor suppressor protein it codes for. Drugs that block these modifications and stimulate UBXN8 activity also arrest tumor cell division. Experiments in mice confirmed that enhanced UBXN8 expression offers a defense against AML progression, suggesting a promising therapeutic approach.