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<h2>Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc</h2> <p><br> <strong>Abstract</strong></p> <p>In 2015, as part of the <a href="https://osf.io/e81xl/wiki/home/" rel="nofollow">Reproducibility Project: Cancer Biology</a>, we published a Registered Report (<a href="https://elifesciences.org/content/4/e07072" rel="nofollow">Kandela et al., 2015</a>), that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (<a href="http://www.cell.com/cell/abstract/S0092-8674%2811%2900943-3?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0092867411009433?showall=true" rel="nofollow">Delmore et al., 2011</a>). 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 <em>MYC</em> transcription, which is similar to what was reported in the original study (Figure 3B; <a href="http://www.cell.com/cell/abstract/S0092-8674%2811%2900943-3?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0092867411009433?showall=true" rel="nofollow">Delmore et al., 2011</a>). 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; <a href="http://www.cell.com/cell/abstract/S0092-8674%2811%2900943-3?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0092867411009433?showall=true" rel="nofollow">Delmore et al., 2011</a>). 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; <a href="http://www.cell.com/cell/abstract/S0092-8674%2811%2900943-3?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0092867411009433?showall=true" rel="nofollow">Delmore et al., 2011</a>), 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.</p> <hr> <h3>Contents</h3> <p><strong>Reports:</strong> Read the <a href="http://dx.doi.org/10.7554/eLife.21253" rel="nofollow">Replication Study</a>, or view the <a href="https://osf.io/2u4nh/" rel="nofollow">preprint versions</a>. </p> <p>To reproduce the Replication Study manuscript text run this in <a href="https://www.rstudio.com" rel="nofollow">R Studio</a> (note: downloads <a href="https://osf.io/sgru9/" rel="nofollow">R markdown file</a> directly from <a href="http://osf.io" rel="nofollow">osf.io</a>):</p> <pre class="highlight"><code>library(httr) library(rmarkdown) GET(&quot;<a href="https://osf.io/sgru9/?action=download" rel="nofollow">https://osf.io/sgru9/?action=download</a>&quot;, write_disk(&quot;Replication_Study_19.Rmd&quot;, overwrite = T)) render(&quot;Replication_Study_19.Rmd&quot;, output_format = &quot;word_document&quot;)</code></pre> <p><br> Also, explore the <a href="https://elifesciences.org/content/4/e07072" rel="nofollow">Registered Report</a> and materials related to the Registered Report <a href="https://osf.io/bjrpc/wiki/home/" rel="nofollow">here</a>.</p> <p><br> <strong>Experiments replicated:</strong> Reproduce and explore the figures, analyses, data, and methods generated in this replication attempt.</p> <ul> <li><a href="https://osf.io/9swnx/wiki/home/" rel="nofollow">Evaluation of MYC expression in JQ1-treated MM.1S-luc cells</a></li> <li> <p>Replication of Figure 3B in Delmore et al., 2011.</p> </li> <li> <p><a href="https://osf.io/pnvtd/wiki/home/" rel="nofollow">Testing the efficacy of JQ1 treatment in mice harboring bioluminescent MM lesions</a></p> </li> <li>Replication of Figures 7C, 7D, and 7E in Delmore et al., 2011.</li> </ul> <p><br> <strong>Meta-analyses:</strong> As a measure of evaluating reproducibility a meta-analysis of each effect was performed. The forest plots, analyses, and data are available <a href="https://osf.io/9snja/wiki/home/" rel="nofollow">here</a>.</p> <p><br> Questions about the project can be directed to <a href="mailto:contact+rpcb@cos.io">contact+rpcb@cos.io</a>.</p>
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