Data from BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor Article Swipe
Hatice Gülçin Özer
,
Dalia El‐Gamal
,
B. J. Powell
,
Zachary A. Hing
,
James S. Blachly
,
Bonnie K. Harrington
,
Shaneice Mitchell
,
Nicole R. Grieselhuber
,
Katie Williams
,
Tzung-Huei Lai
,
Lapo Alinari
,
Robert A. Baiocchi
,
Lindsey T. Brinton
,
Elizabeth Baskin
,
Matthew Cannon
,
Larry Beaver
,
Virginia M. Goettl
,
David Lucas
,
Jennifer A. Woyach
,
Deepa Sampath
,
Amy M. Lehman
,
Lianbo Yu
,
Jiazhong Zhang
,
Yan Ma
,
Ying Zhang
,
Wayne Spevak
,
Songyuan Shi
,
Paul Severson
,
Rafe Shellooe
,
Heidi Carias
,
Garson Tsang
,
Ken C. Dong
,
Todd Ewing
,
Adhirai Marimuthu
,
Christina Tantoy
,
Jason Walters
,
Laura Sanftner
,
Hamid Reza Rezaei
,
Marika Nespi
,
Bernice Matusow
,
Gaston Habets
,
Prabha N. Ibrahim
,
Chao Zhang
,
Ewy A. Mathé
,
Gideon Bollag
,
John C. Byrd
,
Rosa Lapalombella
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/2159-8290.c.6546899.v1
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/2159-8290.c.6546899.v1
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. Cancer Discov; 8(4); 458–77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1158/2159-8290.c.6546899.v1
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4392721769
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4392721769Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1158/2159-8290.c.6546899.v1Digital Object Identifier
- Title
-
Data from BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET InhibitorWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-04-03Full publication date if available
- Authors
-
Hatice Gülçin Özer, Dalia El‐Gamal, B. J. Powell, Zachary A. Hing, James S. Blachly, Bonnie K. Harrington, Shaneice Mitchell, Nicole R. Grieselhuber, Katie Williams, Tzung-Huei Lai, Lapo Alinari, Robert A. Baiocchi, Lindsey T. Brinton, Elizabeth Baskin, Matthew Cannon, Larry Beaver, Virginia M. Goettl, David Lucas, Jennifer A. Woyach, Deepa Sampath, Amy M. Lehman, Lianbo Yu, Jiazhong Zhang, Yan Ma, Ying Zhang, Wayne Spevak, Songyuan Shi, Paul Severson, Rafe Shellooe, Heidi Carias, Garson Tsang, Ken C. Dong, Todd Ewing, Adhirai Marimuthu, Christina Tantoy, Jason Walters, Laura Sanftner, Hamid Reza Rezaei, Marika Nespi, Bernice Matusow, Gaston Habets, Prabha N. Ibrahim, Chao Zhang, Ewy A. Mathé, Gideon Bollag, John C. Byrd, Rosa LapalombellaList of authors in order
- Landing page
-
https://doi.org/10.1158/2159-8290.c.6546899.v1Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.1158/2159-8290.c.6546899.v1Direct OA link when available
- Concepts
-
Chronic lymphocytic leukemia, Computational biology, Profiling (computer programming), BRD4, Leukemia, Biology, Cancer research, Bromodomain, Genetics, Computer science, Gene, Epigenetics, Operating systemTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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