Park Soyoung, Sater Ali H Abdel, Fahrmann Johannes F, Irajizad Ehsan, Cai Yining, Katayama Hiroyuki, Vykoukal Jody, Kobayashi Makoto, Dennison Jennifer B, Garcia-Manero Guillermo, Mullighan Charles G, Gu Zhaohui, Konopleva Marina, Hanash Samir
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2022 Aug 31;14(17):4262. doi: 10.3390/cancers14174262.
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.
含 PHD 和 RING 指结构域的泛素样蛋白（UHRF）家族成员在多种癌症类型中是过表达的假定癌基因。我们评估了急性白血病中 UHRF 家族成员的蛋白质丰度。与急性髓系白血病（AML）相比，在急性淋巴细胞白血病（ALL）中观察到 UHRF1 蛋白明显过表达。对人类白血病转录组数据集的分析显示，与慢性淋巴细胞白血病（CLL）、AML 和慢性髓系白血病（CML）相比，UHRF1 在 B 细胞和 T 细胞 ALL 中一致过表达。体外研究表明，在 B-ALL 和 T-ALL 中，通过 siRNA 介导敲低 UHRF1 可降低细胞活力，这与 c-Myc 蛋白表达降低有关。机制研究表明，UHRF1 直接与 c-Myc 相互作用，通过 CDK4/6-磷酸化视网膜母细胞瘤蛋白（phosphoRb）轴促进 ALL 细胞增殖。我们的研究结果突出了 UHRF1 在调节 c-Myc 蛋白表达方面以前未知的作用，并表明 UHRF1 是 ALL 潜在的治疗靶点。
