BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor

Hatice Gulcin Ozer, Dalia A ElGamal, Ben Powell, Zachary A. Hing, James S. Blachly, Bonnie Harrington, Shaneice Mitchell, Nicole R. Grieselhuber, Katie Williams, Tzung Huei Lai, Lapo Alinari, Robert A. Baiocchi, Lindsey Brinton, Elizabeth Baskin, Matthew Cannon, Larry Beaver, Virginia M. Goettl, David M. Lucas, Jennifer A. Woyach, Deepa Sampath & 27 others Amy M. Lehman, Lianbo Yu, Jiazhong Zhang, Yan Ma, Ying Zhang, Wayne Spevak, Songyuan Shi, Paul Severson, Rafe Shellooe, Heidi Carias, Garson Tsang, Ken Dong, Todd Ewing, Adhirai Marimuthu, Christina Tantoy, Jason Walters, Laura Sanftner, Hamid Rezaei, Marika Nespi, Bernice Matusow, Gaston Habets, Prabha Ibrahim, Chao Zhang, Ewy A. Mathe, Gideon Bollag, John C. Byrd, Rosa Lapalombella

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)458-477
Number of pages20
JournalCancer Discovery
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
Epigenomics
Neoplasms
Critical Pathways
Regulator Genes
Genes
Disease Progression
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor. / Ozer, Hatice Gulcin; ElGamal, Dalia A; Powell, Ben; Hing, Zachary A.; Blachly, James S.; Harrington, Bonnie; Mitchell, Shaneice; Grieselhuber, Nicole R.; Williams, Katie; Lai, Tzung Huei; Alinari, Lapo; Baiocchi, Robert A.; Brinton, Lindsey; Baskin, Elizabeth; Cannon, Matthew; Beaver, Larry; Goettl, Virginia M.; Lucas, David M.; Woyach, Jennifer A.; Sampath, Deepa; Lehman, Amy M.; Yu, Lianbo; Zhang, Jiazhong; Ma, Yan; Zhang, Ying; Spevak, Wayne; Shi, Songyuan; Severson, Paul; Shellooe, Rafe; Carias, Heidi; Tsang, Garson; Dong, Ken; Ewing, Todd; Marimuthu, Adhirai; Tantoy, Christina; Walters, Jason; Sanftner, Laura; Rezaei, Hamid; Nespi, Marika; Matusow, Bernice; Habets, Gaston; Ibrahim, Prabha; Zhang, Chao; Mathe, Ewy A.; Bollag, Gideon; Byrd, John C.; Lapalombella, Rosa.

In: Cancer Discovery, Vol. 8, No. 4, 01.04.2018, p. 458-477.

Research output: Contribution to journalArticle

Ozer, HG, ElGamal, DA, Powell, B, Hing, ZA, Blachly, JS, Harrington, B, Mitchell, S, Grieselhuber, NR, Williams, K, Lai, TH, Alinari, L, Baiocchi, RA, Brinton, L, Baskin, E, Cannon, M, Beaver, L, Goettl, VM, Lucas, DM, Woyach, JA, Sampath, D, Lehman, AM, Yu, L, Zhang, J, Ma, Y, Zhang, Y, Spevak, W, Shi, S, Severson, P, Shellooe, R, Carias, H, Tsang, G, Dong, K, Ewing, T, Marimuthu, A, Tantoy, C, Walters, J, Sanftner, L, Rezaei, H, Nespi, M, Matusow, B, Habets, G, Ibrahim, P, Zhang, C, Mathe, EA, Bollag, G, Byrd, JC & Lapalombella, R 2018, 'BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor', Cancer Discovery, vol. 8, no. 4, pp. 458-477. https://doi.org/10.1158/2159-8290.CD-17-0902
Ozer, Hatice Gulcin ; ElGamal, Dalia A ; Powell, Ben ; Hing, Zachary A. ; Blachly, James S. ; Harrington, Bonnie ; Mitchell, Shaneice ; Grieselhuber, Nicole R. ; Williams, Katie ; Lai, Tzung Huei ; Alinari, Lapo ; Baiocchi, Robert A. ; Brinton, Lindsey ; Baskin, Elizabeth ; Cannon, Matthew ; Beaver, Larry ; Goettl, Virginia M. ; Lucas, David M. ; Woyach, Jennifer A. ; Sampath, Deepa ; Lehman, Amy M. ; Yu, Lianbo ; Zhang, Jiazhong ; Ma, Yan ; Zhang, Ying ; Spevak, Wayne ; Shi, Songyuan ; Severson, Paul ; Shellooe, Rafe ; Carias, Heidi ; Tsang, Garson ; Dong, Ken ; Ewing, Todd ; Marimuthu, Adhirai ; Tantoy, Christina ; Walters, Jason ; Sanftner, Laura ; Rezaei, Hamid ; Nespi, Marika ; Matusow, Bernice ; Habets, Gaston ; Ibrahim, Prabha ; Zhang, Chao ; Mathe, Ewy A. ; Bollag, Gideon ; Byrd, John C. ; Lapalombella, Rosa. / BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor. In: Cancer Discovery. 2018 ; Vol. 8, No. 4. pp. 458-477.
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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.",
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T1 - BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct bet inhibitor

AU - Ozer, Hatice Gulcin

AU - ElGamal, Dalia A

AU - Powell, Ben

AU - Hing, Zachary A.

AU - Blachly, James S.

AU - Harrington, Bonnie

AU - Mitchell, Shaneice

AU - Grieselhuber, Nicole R.

AU - Williams, Katie

AU - Lai, Tzung Huei

AU - Alinari, Lapo

AU - Baiocchi, Robert A.

AU - Brinton, Lindsey

AU - Baskin, Elizabeth

AU - Cannon, Matthew

AU - Beaver, Larry

AU - Goettl, Virginia M.

AU - Lucas, David M.

AU - Woyach, Jennifer A.

AU - Sampath, Deepa

AU - Lehman, Amy M.

AU - Yu, Lianbo

AU - Zhang, Jiazhong

AU - Ma, Yan

AU - Zhang, Ying

AU - Spevak, Wayne

AU - Shi, Songyuan

AU - Severson, Paul

AU - Shellooe, Rafe

AU - Carias, Heidi

AU - Tsang, Garson

AU - Dong, Ken

AU - Ewing, Todd

AU - Marimuthu, Adhirai

AU - Tantoy, Christina

AU - Walters, Jason

AU - Sanftner, Laura

AU - Rezaei, Hamid

AU - Nespi, Marika

AU - Matusow, Bernice

AU - Habets, Gaston

AU - Ibrahim, Prabha

AU - Zhang, Chao

AU - Mathe, Ewy A.

AU - Bollag, Gideon

AU - Byrd, John C.

AU - Lapalombella, Rosa

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

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