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

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. Vakoc

doi:10.1016/j.ccell.2018.10.015

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

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. Vakoc

Research output: Contribution to journal › Article › Research › peer-review

50 Citations (Scopus)

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.

Original language	English
Pages (from-to)	970-981.e8
Number of pages	12
Journal	Cancer Cell
Volume	34
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2018.10.015
Publication status	Published - 10 Dec 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

addiction
CRISPR screen
leukemia
MLL
motif
oncogene
promoter
ZFP64

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10.1016/j.ccell.2018.10.015Licence: CC BY

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Lu, B., Klingbeil, O., Tarumoto, Y., Somerville, T. D. D., Huang, Y. H., Wei, Y., Wai, D. C., Low, J. K. K., Milazzo, J. P., Wu, X. S., Cao, Z., Yan, X., Demerdash, O. E., Huang, G., Mackay, J. P., Kinney, J. B., Shi, J., & Vakoc, C. R. (2018). A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence. Cancer Cell, 34(6), 970-981.e8. https://doi.org/10.1016/j.ccell.2018.10.015

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title = "A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence",

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 = "addiction, CRISPR screen, leukemia, MLL, motif, oncogene, promoter, ZFP64",

author = "Bin Lu and Olaf Klingbeil and Yusuke Tarumoto and Somerville, \{Tim D.D.\} and Huang, \{Yu Han\} and Yiliang Wei and Wai, \{Dorothy C.\} and Low, \{Jason K.K.\} and Milazzo, \{Joseph P.\} and Wu, \{Xiaoli S.\} and Zhendong Cao and Xiaomei Yan and Demerdash, \{Osama E.\} and Gang Huang and Mackay, \{Joel P.\} and Kinney, \{Justin B.\} and Junwei Shi and Vakoc, \{Christopher R.\}",

note = "Funding Information: We would like to thank members of the Vakoc laboratory for helpful discussions and suggestions throughout the course of this study. We thank James C. Mulloy for retroviral human leukemia lines, the CSHL Cancer Center Shared Resources for deep-sequencing and bioinformatics supported by NCI Cancer Center Support grant 5P30CA045508. Additional funding for C.R.V was provided by the Forbeck Foundation, the Pershing Square Sohn Cancer Research Alliance, the Don Monti Foundation, National Institutes of Health grant NCI RO1 CA174793, NCI 5P01CA013106-Project 4, and a Leukemia \& Lymphoma Society Scholar Award. Y.T. is supported by the Lauri Strauss Leukemia Foundation. J.P.M. is supported by a Senior Research Fellowship from the NHMRC. T.D.D.S. is supported by a grant from the State of New York (C150158).C.R.V. is an advisor to KSQ Therapeutics and receives research funding from Boehringer Ingelheim. Funding Information: We would like to thank members of the Vakoc laboratory for helpful discussions and suggestions throughout the course of this study. We thank James C. Mulloy for retroviral human leukemia lines, the CSHL Cancer Center Shared Resources for deep-sequencing and bioinformatics supported by NCI Cancer Center Support grant 5P30CA045508 . Additional funding for C.R.V was provided by the Forbeck Foundation , the Pershing Square Sohn Cancer Research Alliance , the Don Monti Foundation , National Institutes of Health grant NCI RO1 CA174793 , NCI 5P01CA013106 -Project 4, and a Leukemia \& Lymphoma Society Scholar Award. Y.T. is supported by the Lauri Strauss Leukemia Foundation . J.P.M. is supported by a Senior Research Fellowship from the NHMRC . T.D.D.S. is supported by a grant from the State of New York ( C150158 ). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = dec,

day = "10",

doi = "10.1016/j.ccell.2018.10.015",

language = "English",

volume = "34",

pages = "970--981.e8",

journal = "Cancer Cell",

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number = "6",

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Lu, B, Klingbeil, O, Tarumoto, Y, Somerville, TDD, Huang, YH, Wei, Y, Wai, DC, Low, JKK, Milazzo, JP, Wu, XS, Cao, Z, Yan, X, Demerdash, OE, Huang, G, Mackay, JP, Kinney, JB, Shi, J & Vakoc, CR 2018, 'A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence', Cancer Cell, vol. 34, no. 6, pp. 970-981.e8. https://doi.org/10.1016/j.ccell.2018.10.015

TY - JOUR

T1 - A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence

AU - Lu, Bin

AU - Klingbeil, Olaf

AU - Tarumoto, Yusuke

AU - Somerville, Tim D.D.

AU - Huang, Yu Han

AU - Wei, Yiliang

AU - Wai, Dorothy C.

AU - Low, Jason K.K.

AU - Milazzo, Joseph P.

AU - Wu, Xiaoli S.

AU - Cao, Zhendong

AU - Yan, Xiaomei

AU - Demerdash, Osama E.

AU - Huang, Gang

AU - Mackay, Joel P.

AU - Kinney, Justin B.

AU - Shi, Junwei

AU - Vakoc, Christopher R.

N1 - Funding Information: We would like to thank members of the Vakoc laboratory for helpful discussions and suggestions throughout the course of this study. We thank James C. Mulloy for retroviral human leukemia lines, the CSHL Cancer Center Shared Resources for deep-sequencing and bioinformatics supported by NCI Cancer Center Support grant 5P30CA045508. Additional funding for C.R.V was provided by the Forbeck Foundation, the Pershing Square Sohn Cancer Research Alliance, the Don Monti Foundation, National Institutes of Health grant NCI RO1 CA174793, NCI 5P01CA013106-Project 4, and a Leukemia & Lymphoma Society Scholar Award. Y.T. is supported by the Lauri Strauss Leukemia Foundation. J.P.M. is supported by a Senior Research Fellowship from the NHMRC. T.D.D.S. is supported by a grant from the State of New York (C150158).C.R.V. is an advisor to KSQ Therapeutics and receives research funding from Boehringer Ingelheim. Funding Information: We would like to thank members of the Vakoc laboratory for helpful discussions and suggestions throughout the course of this study. We thank James C. Mulloy for retroviral human leukemia lines, the CSHL Cancer Center Shared Resources for deep-sequencing and bioinformatics supported by NCI Cancer Center Support grant 5P30CA045508 . Additional funding for C.R.V was provided by the Forbeck Foundation , the Pershing Square Sohn Cancer Research Alliance , the Don Monti Foundation , National Institutes of Health grant NCI RO1 CA174793 , NCI 5P01CA013106 -Project 4, and a Leukemia & Lymphoma Society Scholar Award. Y.T. is supported by the Lauri Strauss Leukemia Foundation . J.P.M. is supported by a Senior Research Fellowship from the NHMRC . T.D.D.S. is supported by a grant from the State of New York ( C150158 ). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/12/10

Y1 - 2018/12/10

N2 - 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.

AB - 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.

KW - addiction

KW - CRISPR screen

KW - leukemia

KW - MLL

KW - motif

KW - oncogene

KW - promoter

KW - ZFP64

UR - https://www.scopus.com/pages/publications/85058593248

U2 - 10.1016/j.ccell.2018.10.015

DO - 10.1016/j.ccell.2018.10.015

M3 - Article

C2 - 30503706

AN - SCOPUS:85058593248

SN - 1535-6108

VL - 34

SP - 970-981.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

UN SDGs

Keywords

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