Novel UHRF1-MYC Axis in Acute Lymphoblastic Leukemia
Soyoung Park, Ali H. Abdel Sater, Johannes F. Fahrmann, Ehsan Irajizad, Yining Cai, Hiroyuki Katayama, Jody V. Vykoukal, Makoto Kobayashi, Jennifer B. Dennison, Guillermo Garcia‐Manero, Charles G. Mullighan, Zhaohui Gu, Marina Konopleva, Samir Hanash
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.