A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence
Publication date: Available online 29 November 2018Source: Cancer CellAuthor(s): Bin Lu, Olaf Klingbeil, Yusuke Tarumoto, Tim D.D. Somerville, Yu-Han Huang, Yiliang Wei, Dorothy C. Wai, Jason K.K. Low, Joseph P. Milazzo, Xiaoli S. Wu, Zhendong Cao, Xiaomei Yan, Osama E. Demerdash, Gang Huang, Joel P. Mackay, Justin B. Kinney, Junwei Shi, Christopher R. VakocSummaryThe Mixed Lineage Leukemia gene (MLL) is altered in leukemia by chromosomal translocations to produce oncoproteins composed of the MLL N-terminus fused to the C-terminus of a partner protein. Here, we used domain-focused CRISPR screening to identify ZFP64 as an essential transcription factor in MLL-rearranged leukemia. We show that the critical function of ZFP64 in leukemia is to maintain MLL expression via binding to the MLL promoter, which is the most enriched location of ZFP64 occupancy in the human genome. The specificity of ZFP64 for MLL is accounted for by an exceptional density of ZFP64 motifs embedded within the MLL promoter. These findings demonstrate how a sequence anomaly of an oncogene promoter can impose a transcriptional addiction in cancer.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research