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Cancer Cell. 2018 Dec 10;34(6):970-981.e8. doi: 10.1016/j.ccell.2018.10.015. Epub 2018 Nov 29.

A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
3
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
5
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jushi@upenn.edu.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.

Abstract

The 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.

KEYWORDS:

CRISPR screen; MLL; ZFP64; addiction; leukemia; motif; oncogene; promoter

PMID:
30503706
PMCID:
PMC6554023
DOI:
10.1016/j.ccell.2018.10.015
[Indexed for MEDLINE]
Free PMC Article

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