Dataset Information

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

ABSTRACT: 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 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq 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.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4996374 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Zhao Yue Y Liu Qi Q Acharya Pankaj P Stengel Kristy R KR Sheng Quanhu Q Zhou Xiaofan X Kwak Hojoong H Fischer Melissa A MA Bradner James E JE Strickland Stephen A SA Mohan Sanjay R SR Savona Michael R MR Venters Bryan J BJ Zhou Ming-Ming MM Lis John T JT Hiebert Scott W SW

Cell reports 20160804 7

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 cel ...[more]

PMID: 27498870

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Project description:BACKGROUND & AIMS:Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease. However, distinct from gastroesophageal reflux disease, rumination and supragastric belching are more responsive to behavioral interventions than to acid-suppressive and antireflux therapies. Postprandial high-resolution impedance manometry (PP-HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP-HRIM, and identified patient features associated with postprandial profiles among patients with nonresponse to proton pump inhibitors (PPIs). METHODS:We performed a retrospective analysis of PP-HRIM studies performed on 94 adults (mean age, 50.6 y; 62% female) evaluated for PPI nonresponsiveness at an esophageal referral center, from January 2010 through May 2016. Following a standard esophageal manometry protocol, patients ingested a solid refluxogenic test meal (identified by patients as one that induces symptoms) with postprandial monitoring up to 90 minutes (median, 50 min). Patients were assigned to 1 of 4 postprandial profiles: normal; reflux only (>6 transient lower esophageal sphincter relaxations (TLESRs)/h); supragastric belch (>2 supragastric belches/h), with or without TLESR; or rumination (?1 rumination episode/h) with or without TLESR and supragastric belching. The primary outcome was postprandial profile. RESULTS:Of the study participants, 24% had a normal postprandial profile, 14% had a reflux-only profile, 42% had a supragastric belch profile, and 20% had a rumination profile. In multinomial regression analysis, the rumination group most frequently presented with regurgitation, the supragastric belch and rumination groups were younger in age, and the reflux-only group had a lower esophagogastric junction contractile integral. The number of weakly acidic reflux events measured by impedance-pH monitoring in patients receiving PPI therapy was significantly associated with frequency of rumination episodes and supragastric belches. CONCLUSIONS:In a retrospective analysis of 94 nonresponders to PPI therapy evaluated by PP-HRIM, we detected an abnormal postprandial pattern in 76% of cases: 42% of these were characterized as supragastric belching, 20% as rumination, and 14% as reflux only. Age, esophagogastric junction contractility, impedance-pH profiles, and symptom presentation differed significantly among groups. PP-HRIM can be used in the clinic to evaluate mechanisms of PPI nonresponse.

Dataset Information

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

Publications

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

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