@article{20cb0aa6194842518c5b81a193773621,
title = "BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor",
abstract = "Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. SIGNIFICANCE: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL.",
author = "Ozer, {Hatice Gulcin} and Dalia El-Gamal and Ben Powell and Hing, {Zachary A.} and Blachly, {James S.} and Bonnie Harrington and Shaneice Mitchell and Grieselhuber, {Nicole R.} and Katie Williams and Lai, {Tzung Huei} and Lapo Alinari and Baiocchi, {Robert A.} and Lindsey Brinton and Elizabeth Baskin and Matthew Cannon and Larry Beaver and Goettl, {Virginia M.} and Lucas, {David M.} and Woyach, {Jennifer A.} and Deepa Sampath and Lehman, {Amy M.} and Lianbo Yu and Jiazhong Zhang and Yan Ma and Ying Zhang and Wayne Spevak and Songyuan Shi and Paul Severson and Rafe Shellooe and Heidi Carias and Garson Tsang and Ken Dong and Todd Ewing and Adhirai Marimuthu and Christina Tantoy and Jason Walters and Laura Sanftner and Hamid Rezaei and Marika Nespi and Bernice Matusow and Gaston Habets and Prabha Ibrahim and Chao Zhang and Mathe, {Ewy A.} and Gideon Bollag and Byrd, {John C.} and Rosa Lapalombella",
note = "Funding Information: We are grateful to the patients and healthy volunteers who provided blood for the above studies and to the OSU Comprehensive Cancer Center Leukemia Tissue Bank (supported by NCIP30 CA016058) for sample procurement. X-ray diffraction data were collected at beamline 8.3.1 at the Advanced Light Source (Lawrence Berkeley National Laboratory), beamline 08ID-1 at Canadian Light Source, and beamline 7.1 at the Stanford Synchrotron Radiation Lightsource (a directorate of the SLAC National Accelerator Laboratory). The authors would also like to acknowledge Alan Flechtner, HTL, and The Ohio State University Veterinary Histology Laboratory for their assistance in all immunohistochemical studies, also supported by NCIP30 CA016058. This work was supported by the NCI (K99/R00 CA208017, R01 CA177292, R01 CA206658, R01 CA214046, and R35 CA198183), a Research Scholar grant (129863-RSG-16-158-01-CDD) from the American Cancer Society, NCIP30 (CA 016058), The OSU Comprehensive Cancer Center using Pelotonia funds, and further research support to the Byrd Laboratory from the Four Winds Foundation, the D. Warren Brown Foundation, the Connie Brown CLL Research Fund, and the Sullivan CLL Research Foundation. This study makes use of RNAsequencing data generated by the Blueprint Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu. Funding for the project was provided to the Blueprint Consortium by the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282510 BLUEPRINT. Funding Information: We are grateful to the patients and healthy volunteers who provided blood for the above studies and to the OSU Comprehensive Cancer Center Leukemia Tissue Bank (supported by NCIP30 CA016058) for sample procurement. X-ray diffraction data were collected at beamline 8.3.1 at the Advanced Light Source (Lawrence Berkeley National Laboratory), beamline 08ID-1 at Canadian Light Source, and beamline 7.1 at the Stanford Synchrotron Radiation Lightsource (a directorate of the SLAC National Accelerator Laboratory). The authors would also like to acknowledge Alan Flechtner, HTL, and The Ohio State University Veterinary Histology Laboratory for their assistance in all immunohistochemical studies, also supported by NCIP30 CA016058. This work was supported by the National Cancer Institute (K99/R00 CA208017, R01 CA177292, R01 CA206658, R01 CA214046, and R35 CA198183), a Research Scholar grant (129863-RSG-16-158-01-CDD) from the American Cancer Society, NCIP30 (CA 016058), The OSU Comprehensive Cancer Center using Pelotonia funds, and further research support to the Byrd Laboratory from the Four Winds Foundation, the D. Warren Brown Foundation, the Connie Brown CLL Research Fund, and the Sullivan CLL Research Foundation. This study makes use of RNA-sequencing data generated by the Blueprint Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu. Funding for the project was provided to the Blueprint Consortium by the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282510 BLUEPRINT. Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = apr,
doi = "10.1158/2159-8290.CD-17-0902",
language = "English (US)",
volume = "8",
pages = "458--477",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "4",
}