Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A associated protein 30 (SAP30) through two amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, these studies reveal the mechanisms for altered epigenetic programs in AML and provide a promising targeted therapeutic strategy against AML. UHRF1 CUT-TAG was performed with UHRF1 antibody in Kasumi-1 and THP-1 cells (AML cells). We used UHRF1 shRNA to induce UHRF1 knockdown in Kasumi-1 and THP-1 cells. Kasumi-1 and THP-1 cells were transduced with UHRF1 shRNA and then AML cells were selected by puromycine for 48h,finally these AML cells were subjected to RNA-seq analysis. Kasumi-1 and THP-1 cells were treated with UHRF1 inhibitor UF146 for 24h and these cells were subjected to RNA-seq analysis.