Core transcriptional regulatory circuitry molecule ZNF217 promotes AML cell proliferation by up-regulating MYB

Leukemia is characterized by multiple rearrangements of signal transduction genes and overexpression of nonmutated genes, such as transcription factors (TFs) genes. Super-enhancers (SEs) are prevalent in human cancers and are associated with the accumulation of numerous core TFs. SEs drive the expression of core TF genes by delivering robust transcriptional activation signals. Additionally, core TFs sustain the stability and activity of SEs through mutual auto-regulation loops, creating a positive feedback loop known as the Core Transcriptional Regulation Circuit (CRC). Using ChIP-seq data, we identified the involvement of the SE-related gene ZNF217 in acute myeloid leukemia (AML), in which its functional role and underlying mechanism remain unclear. We demonstrated that ZNF217, ELF1, MEF2D, RUNX2, and FOXP1 are likely integral components of the AML CRC through various experimental techniques, including CUT&Tag, short hairpin RNA (shRNA) transduction, and Luciferase reporter assays. Notably, ZNF217 was determined to be indispensable for the proliferation and viability of AML cells both <i>in vitro</i> and <i>in vivo</i>. Subsequent analysis of RNA-seq and CUT&Tag results identified MYB as a key direct target of ZNF217. Overall, our research highlights ZNF217 as a critical oncogene in AML and offers new insights into the transcriptional regulatory mechanisms at play in AML.