Novel UHRF1-MYC Axis in Acute Lymphoblastic Leukemia

SIMPLE SUMMARY: We provided evidence that ubiquitin-like, containing PHD and RING finger domain, 1 (UHRF1) is overexpressed in acute lymphocytic leukemia (ALL). We further showed that UHRF1 directly interacts and regulates c-Myc expression to enable ALL cell growth through the cMYC-CDK4/6 phosphoRb-signaling axis. ABSTRACT: Ubiquitin-like, containing PHD and RING finger domain, (UHRF) family members are overexpressed putative oncogenes in several cancer types. We evaluated the protein abundance of UHRF family members in acute leukemia. A marked overexpression of UHRF1 protein was observed in ALL compared with AML. An analysis of human leukemia transcriptomic datasets revealed concordant overexpression of UHRF1 in B-Cell and T-Cell ALL compared with CLL, AML, and CML. In-vitro studies demonstrated reduced cell viability with siRNA-mediated knockdown of UHRF1 in both B-ALL and T-ALL, associated with reduced c-Myc protein expression. Mechanistic studies indicated that UHRF1 directly interacts with c-Myc, enabling ALL expansion via the CDK4/6-phosphoRb axis. Our findings highlight a previously unknown role of UHRF1 in regulating c-Myc protein expression and implicate UHRF1 as a potential therapeutic target in ALL.