Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc.

Abstract:

:In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7C-D; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (-)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result.

journal_name

Elife

journal_title

eLife

authors

Aird F,Kandela I,Mantis C,Reproducibility Project: Cancer Biology.

doi

10.7554/eLife.21253

subject

Has Abstract

pub_date

2017-01-19 00:00:00

issn

2050-084X

journal_volume

6

pub_type

杂志文章

相关文献

eLife文献大全
  • Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit.

    abstract::We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture pas...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.58042

    authors: Díaz-Alonso J,Morishita W,Incontro S,Simms J,Holtzman J,Gill M,Mucke L,Malenka RC,Nicoll RA

    更新日期:2020-08-24 00:00:00

  • Activity patterns of serotonin neurons underlying cognitive flexibility.

    abstract::Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to stu...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.20552

    authors: Matias S,Lottem E,Dugué GP,Mainen ZF

    更新日期:2017-03-21 00:00:00

  • The Sec61 translocon limits IRE1α signaling during the unfolded protein response.

    abstract::IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.27187

    authors: Sundaram A,Plumb R,Appathurai S,Mariappan M

    更新日期:2017-05-15 00:00:00

  • Gene autoregulation by 3' UTR-derived bacterial small RNAs.

    abstract::Negative feedback regulation, that is the ability of a gene to repress its own synthesis, is the most abundant regulatory motif known to biology. Frequently reported for transcriptional regulators, negative feedback control relies on binding of a transcription factor to its own promoter. Here, we report a novel mechan...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.58836

    authors: Hoyos M,Huber M,Förstner KU,Papenfort K

    更新日期:2020-08-03 00:00:00

  • Medial orbitofrontal inactivation does not affect economic choice.

    abstract::How are decisions made between different goods? One theory spanning several fields of neuroscience proposes that their values are distilled to a single common neural currency, the calculation of which allows for rational decisions. The orbitofrontal cortex (OFC) is thought to play a critical role in this process, base...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.38963

    authors: Gardner MP,Conroy JC,Styer CV,Huynh T,Whitaker LR,Schoenbaum G

    更新日期:2018-10-03 00:00:00

  • v-SNARE transmembrane domains function as catalysts for vesicle fusion.

    abstract::Vesicle fusion is mediated by an assembly of SNARE proteins between opposing membranes, but it is unknown whether transmembrane domains (TMDs) of SNARE proteins serve mechanistic functions that go beyond passive anchoring of the force-generating SNAREpin to the fusing membranes. Here, we show that conformational flexi...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.17571

    authors: Dhara M,Yarzagaray A,Makke M,Schindeldecker B,Schwarz Y,Shaaban A,Sharma S,Böckmann RA,Lindau M,Mohrmann R,Bruns D

    更新日期:2016-06-25 00:00:00

  • Shearing in flow environment promotes evolution of social behavior in microbial populations.

    abstract::How producers of public goods persist in microbial communities is a major question in evolutionary biology. Cooperation is evolutionarily unstable, since cheating strains can reproduce quicker and take over. Spatial structure has been shown to be a robust mechanism for the evolution of cooperation. Here we study how s...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.34862

    authors: Uppal G,Vural DC

    更新日期:2018-05-22 00:00:00

  • Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry.

    abstract::Multiple sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord that are highly variable in terms of cellular content. Here, we used imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within staged MS lesions. To test the potential for IMC to ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.48051

    authors: Ramaglia V,Sheikh-Mohamed S,Legg K,Park C,Rojas OL,Zandee S,Fu F,Ornatsky O,Swanson EC,Pitt D,Prat A,McKee TD,Gommerman JL

    更新日期:2019-08-01 00:00:00

  • Gene regulation gravitates toward either addition or multiplication when combining the effects of two signals.

    abstract::Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or multiplicative combined responses, but a systematic genome-wide evalu...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.59388

    authors: Sanford EM,Emert BL,Coté A,Raj A

    更新日期:2020-12-07 00:00:00

  • Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments.

    abstract::The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. We quantified actin filament order in human cells using fluorescence polarization microscopy and found that cleavage furrow ingression...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.30867

    authors: Spira F,Cuylen-Haering S,Mehta S,Samwer M,Reversat A,Verma A,Oldenbourg R,Sixt M,Gerlich DW

    更新日期:2017-11-06 00:00:00

  • Nanoresolution real-time 3D orbital tracking for studying mitochondrial trafficking in vertebrate axons in vivo.

    abstract::We present the development and in vivo application of a feedback-based tracking microscope to follow individual mitochondria in sensory neurons of zebrafish larvae with nanometer precision and millisecond temporal resolution. By combining various technical improvements, we tracked individual mitochondria with unpreced...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.46059

    authors: Wehnekamp F,Plucińska G,Thong R,Misgeld T,Lamb DC

    更新日期:2019-06-10 00:00:00

  • MELK expression correlates with tumor mitotic activity but is not required for cancer growth.

    abstract::The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tu...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.32838

    authors: Giuliano CJ,Lin A,Smith JC,Palladino AC,Sheltzer JM

    更新日期:2018-02-08 00:00:00

  • Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization.

    abstract::Skeletal muscle degeneration is a complication arising from a variety of chronic diseases including advanced cancer. Pro-inflammatory cytokine TNF-α plays a pivotal role in mediating cancer-related skeletal muscle degeneration. Here, we show a novel function for retinoblastoma protein (Rb), where Rb causes sarcomeric ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.01228

    authors: Araki K,Kawauchi K,Hirata H,Yamamoto M,Taya Y

    更新日期:2013-12-03 00:00:00

  • Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli.

    abstract::While specific mutations allow organisms to adapt to stressful environments, most changes in an organism's DNA negatively impact fitness. The mutation rate is therefore strictly regulated and often considered a slowly-evolving parameter. In contrast, we demonstrate an unexpected flexibility in cellular mutation rates ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.22939

    authors: Swings T,Van den Bergh B,Wuyts S,Oeyen E,Voordeckers K,Verstrepen KJ,Fauvart M,Verstraeten N,Michiels J

    更新日期:2017-05-02 00:00:00

  • Patterned perturbation of inhibition can reveal the dynamical structure of neural processing.

    abstract::Perturbation of neuronal activity is key to understanding the brain's functional properties, however, intervention studies typically perturb neurons in a nonspecific manner. Recent optogenetics techniques have enabled patterned perturbations, in which specific patterns of activity can be invoked in identified target n...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.52757

    authors: Sadeh S,Clopath C

    更新日期:2020-02-19 00:00:00

  • NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency.

    abstract::The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex con...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.54993

    authors: Marques JG,Gryder BE,Pavlovic B,Chung Y,Ngo QA,Frommelt F,Gstaiger M,Song Y,Benischke K,Laubscher D,Wachtel M,Khan J,Schäfer BW

    更新日期:2020-08-03 00:00:00

  • Control of entropy in neural models of environmental state.

    abstract::Humans and animals construct internal models of their environment in order to select appropriate courses of action. The representation of uncertainty about the current state of the environment is a key feature of these models that controls the rate of learning as well as directly affecting choice behaviour. To maintai...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.39404

    authors: Muller TH,Mars RB,Behrens TE,O'Reilly JX

    更新日期:2019-02-28 00:00:00

  • An ambulance for retinol.

    abstract::During inflammation, serum amyloid A proteins transport retinol to infected tissues. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.04246

    authors: Ganal SC,MacPherson AJ

    更新日期:2014-09-02 00:00:00

  • Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.

    abstract::Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mic...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.01888

    authors: Cipolat S,Hoste E,Natsuga K,Quist SR,Watt FM

    更新日期:2014-05-05 00:00:00

  • Bugs battle stress from hot blood.

    abstract::A heat exchange mechanism in the head of kissing bugs helps to prevent stress and regulate their temperature while they feed on warm blood. ...

    journal_title:eLife

    pub_type: 评论,杂志文章

    doi:10.7554/eLife.33035

    authors: Benoit JB,Denlinger DL

    更新日期:2017-11-21 00:00:00

  • Rapid whole brain imaging of neural activity in freely behaving larval zebrafish (Danio rerio).

    abstract::The internal brain dynamics that link sensation and action are arguably better studied during natural animal behaviors. Here, we report on a novel volume imaging and 3D tracking technique that monitors whole brain neural activity in freely swimming larval zebrafish (Danio rerio). We demonstrated the capability of our ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.28158

    authors: Cong L,Wang Z,Chai Y,Hang W,Shang C,Yang W,Bai L,Du J,Wang K,Wen Q

    更新日期:2017-09-20 00:00:00

  • TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids.

    abstract::Plasma membrane lipid composition must be maintained during growth and under environmental insult. In yeast, signaling mediated by TOR Complex 2 (TORC2)-dependent protein kinase Ypk1 controls lipid abundance and distribution in response to membrane stress. Ypk1, among other actions, alleviates negative regulation of L...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.03779

    authors: Muir A,Ramachandran S,Roelants FM,Timmons G,Thorner J

    更新日期:2014-10-03 00:00:00

  • KATANIN-dependent mechanical properties of the stigmatic cell wall mediate the pollen tube path in Arabidopsis.

    abstract::Successful fertilization in angiosperms depends on the proper trajectory of pollen tubes through the pistil tissues to reach the ovules. Pollen tubes first grow within the cell wall of the papilla cells, applying pressure to the cell. Mechanical forces are known to play a major role in plant cell shape by controlling ...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.57282

    authors: Riglet L,Rozier F,Kodera C,Bovio S,Sechet J,Fobis-Loisy I,Gaude T

    更新日期:2020-09-01 00:00:00

  • Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.

    abstract::Islet amyloidosis by IAPP contributes to pancreatic β-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat IN...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.12977

    authors: Abedini A,Plesner A,Cao P,Ridgway Z,Zhang J,Tu LH,Middleton CT,Chao B,Sartori DJ,Meng F,Wang H,Wong AG,Zanni MT,Verchere CB,Raleigh DP,Schmidt AM

    更新日期:2016-05-23 00:00:00

  • Correction: The manifold structure of limb coordination in walking Drosophila.

    abstract:: ...

    journal_title:eLife

    pub_type: 已发布勘误

    doi:10.7554/eLife.65214

    authors: DeAngelis BD,Zavatone-Veth JA,Clark DA

    更新日期:2020-12-04 00:00:00

  • Neural coding in barrel cortex during whisker-guided locomotion.

    abstract::Animals seek out relevant information by moving through a dynamic world, but sensory systems are usually studied under highly constrained and passive conditions that may not probe important dimensions of the neural code. Here, we explored neural coding in the barrel cortex of head-fixed mice that tracked walls with th...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.12559

    authors: Sofroniew NJ,Vlasov YA,Hires SA,Freeman J,Svoboda K

    更新日期:2015-12-23 00:00:00

  • Role of SAGA in the asymmetric segregation of DNA circles during yeast ageing.

    abstract::In eukaryotes, intra-chromosomal recombination generates DNA circles, but little is known about how cells react to them. In yeast, partitioning of such circles to the mother cell at mitosis ensures their loss from the population but promotes replicative ageing. Nevertheless, the mechanisms of partitioning are debated....

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.03790

    authors: Denoth-Lippuner A,Krzyzanowski MK,Stober C,Barral Y

    更新日期:2014-11-17 00:00:00

  • High-throughput synapse-resolving two-photon fluorescence microendoscopy for deep-brain volumetric imaging in vivo.

    abstract::Optical imaging has become a powerful tool for studying brains in vivo. The opacity of adult brains makes microendoscopy, with an optical probe such as a gradient index (GRIN) lens embedded into brain tissue to provide optical relay, the method of choice for imaging neurons and neural activity in deeply buried brain s...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.40805

    authors: Meng G,Liang Y,Sarsfield S,Jiang WC,Lu R,Dudman JT,Aponte Y,Ji N

    更新日期:2019-01-04 00:00:00

  • Laminin signals initiate the reciprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs.

    abstract::How mammalian tissues maintain their architecture and tissue-specificity is poorly understood. Previously, we documented both the indispensable role of the extracellular matrix (ECM) protein, laminin-111 (LN1), in the formation of normal breast acini, and the phenotypic reversion of cancer cells to acini-like structur...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.26148

    authors: Furuta S,Ren G,Mao JH,Bissell MJ

    更新日期:2018-03-21 00:00:00

  • The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1.

    abstract::Mammalian HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthetic pathway and the therapeutic target of statins, is post-transcriptionally regulated by sterol-accelerated degradation. Under cholesterol-replete conditions, HMGCR is ubiquitinated and degraded, but the identity of the E3 ubiqu...

    journal_title:eLife

    pub_type: 杂志文章

    doi:10.7554/eLife.40009

    authors: Menzies SA,Volkmar N,van den Boomen DJ,Timms RT,Dickson AS,Nathan JA,Lehner PJ

    更新日期:2018-12-13 00:00:00