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.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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A549 Cells
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Animals
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Cell Line, Tumor
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Leukemic
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HEK293 Cells
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High-Throughput Nucleotide Sequencing
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Humans
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K562 Cells
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Leukemia, Biphenotypic, Acute / genetics*
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Leukemia, Biphenotypic, Acute / metabolism
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Leukemia, Biphenotypic, Acute / pathology
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Promoter Regions, Genetic / genetics*
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THP-1 Cells
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Translocation, Genetic*
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Transplantation, Heterologous
Substances
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DNA-Binding Proteins
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Oncogene Proteins, Fusion
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Transcription Factors
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ZFP64 protein, human
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Myeloid-Lymphoid Leukemia Protein