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Elife. 2017 Jun 27;6. pii: e25306. doi: 10.7554/eLife.25306.

Replication Study: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

Author information

1
University of Pennsylvania, Perelman School of Medicine, Stem Cell and Xenograft Core, Philadelphia, United States.
2
ProNovus Bioscience, LLC, Mountain View, United States.

Abstract

In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al., 2011). Further, I-BET151 resulted in a statistically significant decrease in BCL2 expression in MV4;11 cells, but not in K-562 cells; again this is similar to the findings reported in the original study (Figure 3D; Dawson et al., 2011). We did not find a statistically significant difference in survival when testing I-BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported increased survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Differences between the original study and this replication attempt, such as different conditioning regimens and I-BET151 doses, are factors that might have influenced the outcome. We also found I-BET151 treatment resulted in a lower median disease burden compared to vehicle control in all tissues analyzed, similar to the example reported in the original study (Supplementary Figure 16A; Dawson et al., 2011). Finally, we report meta-analyses for each result.

KEYWORDS:

Reproducibility Project: Cancer Biology; bromodomain inhibitor; cancer biology; human; leukemia; metascience; mouse; replication; reproducibility

PMID:
28653617
PMCID:
PMC5487217
DOI:
10.7554/eLife.25306
[Indexed for MEDLINE]
Free PMC Article

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