High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML

被引：63

作者：

Zhao, Yue ^{[1
]}

Liu, Qi ^{[2
,3
]}

Acharya, Pankaj ^{[1
]}

Stengel, Kristy R. ^{[1
]}

Sheng, Quanhu ^{[2
]}

Zhou, Xiaofan ^{[4
]}

Kwak, Hojoong ^{[5
]}

Fischer, Melissa A. ^{[6
]}

Bradner, James E. ^{[7
]}

Strickland, Stephen A. ^{[6
,8
]}

Mohan, Sanjay R. ^{[6
,8
]}

Savona, Michael R. ^{[6
,8
]}

Venters, Bryan J. ^{[9
]}

Zhou, Ming-Ming ^{[10
]}

Lis, John T. ^{[5
]}

Hiebert, Scott W. ^{[1
,8
]}

机构：

[1] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Ctr Quantitat Sci, Sch Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Biomed Informat, Sch Med, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37212 USA

[5] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA

[6] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA

[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[8] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[9] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[10] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 07期

关键词：

ACUTE MYELOID-LEUKEMIA; TRANSCRIPTION ELONGATION-FACTOR; II-DEPENDENT TRANSCRIPTION; BROMODOMAIN PROTEIN BRD4; P-TEFB; C-KIT; CELL-LINES; MUTATIONS; CANCER; INITIATION;

D O I：

10.1016/j.celrep.2016.07.032

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8; 21) AML. PRO-seq also identified an enhancer 30 to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PROseq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.

引用

页码：2003 / 2016

页数：14