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Experiment Overview

Repository ID: FR-FCM-ZY68 Experiment name: Replication Study: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia MIFlowCyt score: 100.00%
Primary researcher: Xiaochuan Shan PI/manager: Timothy Errington Uploaded by: Timothy Errington
Experiment dates: 2015-09-17 - 2016-08-26 Dataset uploaded: May 2017 Last updated: Jun 2017
Keywords: [bromodomain inhibitor] [mixed-lineage leukemia] [replication] [reproducibility] [metascience] [Reproducibility Project: Cancer Biology] Manuscripts: [28653617]
Organizations: University of Pennsylvania, Perelman School of Medicine, Stem Cell and Xenograft Core, Philadelphia, Pennsylvania (United States)
Center for Open Science, Charlottesville, VA (United States of America)
Science Exchange, Palo Alto, CA (United States of America)
Purpose: This experiment assesses the efficacy of I-BET151 as a therapeutic agent in a xenograft mouse model of leukemia. Immunocompromised mice were injected with preparations of MV4;11 cells and disease progressed until detectable. At that time, mice were treated either with I-BET151 or vehicle control. The presence and degree of disease progression was determined by measuring the number of human leukemia cells present in the peripheral blood (PM), spleen (SPL), and bone marrow (BM) of leukemic xenograft mice. Leukemic mice treated with I-BET151 will be compared to mice treated with vehicle control to determine if I-BET151 treatment increases survival of the mice. Additionally, tumor burden and cell death were monitored to test if I-BET151 decreased tumor burden and increased cell death, compared to vehicle control. This protocol replicates the experiments reported in Figure 4B,D and Supp. Figure 16A of Dawson et al., 2011.
Conclusion: Testing I-BET151 efficacy in a disseminated xenograft MLL mouse model we did not find a statistically significant difference in survival, whereas the original study reported an increase in survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Monitoring the extent of disease burden in this mouse model, we 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). Observationally, there was no notable difference in cell death in the peripheral blood or spleen, with a minor decrease in both apoptotic (Annexin V+PI-) and necrotic cells (Annexin V+PI+) observed in the bone marrow of I-BET151 treated mice compared to vehicle control. Importantly, deviations in this replication attempt compared to the original study, such as a different conditioning regimen and a decreased I-BET151 dose, are factors that might have influenced the outcome.
Comments: This is experiment is part of the Reproducibility Project: Cancer Biology (https://osf.io/e81xl/wiki/home/). The Reproducibility Project: Cancer Biology (RP:CB) is a collaboration between the Center for Open Science and Science Exchange that seeks to address concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology.
Funding: The Reproducibility Project: Cancer Biology is funded by the Laura and John Arnold Foundation, provided to the Center for Open Science in collaboration with Science Exchange. The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Quality control: The cell lines used in this experiment underwent STR profiling to confirm their identity and sent for mycoplasma testing to ensure there is no contamination. Additionally, cells used for xenograft injection were screened against a Rodent Pathogen Panel to ensure no contamination prior to injection. The animals were randomized prior to treatment. An isotype control antibody was used to confirm the specificity of the HLA-A,B,C antibody. Additionally, no antibody and MV4;11 cells (as positive control) were used to ensure specificity. Additional detailed experimental notes, data, and analysis are available on the Open Science Framework (OSF) (https://osf.io/hcqqy/)


Experiment variables

Timepoints
· 3 week bleeding 5150.004 · 5151 lysed.027 · 5151.005 · 5152.006 · 5153.007 · 5154.008 · 5155 lysed.028 · 5155.009 · 5156.010 · 5158.011 · 5159.012 · 5160.013 · 5162.014 · 5163.015 · 5164.016 · 5165.017 · 5166.018 · 5167.019 · 5170.020 · 5171.021 · 5173.022 · 5174.023 · 5175.024 · 5176.025 · 5177.026 · MV-4-11.003 · iso.002 · no Ab.001
· 5 week bleeding ACK 5150.003 · ACK 5151.004 · ACK 5152.005 · ACK 5153.006 · ACK 5154.007 · ACK 5155.008 · ACK 5156.009 · ACK 5158.010 · ACK 5159.011 · ACK 5160.012 · ACK 5162.013 · ACK 5163.014 · ACK 5164.015 · ACK 5165.016 · ACK 5166.017 · ACK 5167.018 · ACK 5170.019 · ACK 5171.020 · ACK 5173.021 · ACK 5174.022 · ACK 5175.023 · ACK 5176.024 · ACK 5177.025 · Beads 5150.026 · Beads 5151.027 · Beads 5152.028 · Beads 5155.029 · Beads 5156.030 · Beads 5158.031 · Beads 5159.032 · Beads 5160.033 · Beads 5163.034 · Beads 5165.035 · Beads 5166.036 · Beads 5167.037 · Beads 5170.038 · Beads 5171.039 · Beads 5173.040 · Beads 5174.041 · Beads 5175.042 · Beads 5176.043 · Beads 5177.044 · MNC POS.002 · beads only.001

Conditions
· Maximum tolerated dose GRP1 BM 3386.024 · GRP1 BM 3392.025 · GRP1 BM 3393.026 · GRP1 BM 3397.027 · GRP1 BM 3399.028 · GRP1 PB 3386.006 · GRP1 PB 3392.007 · GRP1 PB 3393.008 · GRP1 PB 3397.009 · GRP1 PB 3399.010 · GRP1 SPL 3386.042 · GRP1 SPL 3392.043 · GRP1 SPL 3393.044 · GRP1 SPL 3397.045 · GRP1 SPL 3399.046 · GRP2 BM 3387.029 · GRP2 BM 3390.030 · GRP2 BM 3394.031 · GRP2 BM 3396.032 · GRP2 BM 3398.033 · GRP2 PB 3387.011 · GRP2 PB 3390.012 · GRP2 PB 3394.013 · GRP2 PB 3396.014 · GRP2 PB 3398.015 · GRP2 SPL 3387.047 · GRP2 SPL 3390.048 · GRP2 SPL 3394.049 · GRP2 SPL 3396.050 · GRP2 SPL 3398.051 · GRP3 BM 3381.034 · GRP3 BM 3382.035 · GRP3 BM 3383.036 · GRP3 BM 3384.037 · GRP3 BM 3388.038 · GRP3 PB 3381.016 · GRP3 PB 3382.017 · GRP3 PB 3383.018 · GRP3 PB 3384.019 · GRP3 PB 3388.020 · GRP3 SPL 3381.052 · GRP3 SPL 3382.053 · GRP3 SPL 3383.054 · GRP3 SPL 3384.055 · GRP3 SPL 3388.056 · GRP4 BM 3389.039 · GRP4 BM 3391.040 · GRP4 BM 3395.041 · GRP4 PB 3389.021 · GRP4 PB 3391.022 · GRP4 PB 3395.023 · GRP4 SPL 3389.057 · GRP4 SPL 3391.058 · GRP4 SPL 3395.059 · MV-4-11.002 · MV-4-11.005 · grp 1 ISOTYPE.004 · grp 1 isotype.003 · no Ab.001-(1)
· Efficacy 5150.004 · 5151 lysed.027 · 5151.005 · 5152.006 · 5153.007 · 5154.008 · 5155 lysed.028 · 5155.009 · 5156.010 · 5158.011 · 5159.012 · 5160.013 · 5162.014 · 5163.015 · 5164.016 · 5165.017 · 5166.018 · 5167.019 · 5170.020 · 5171.021 · 5173.022 · 5174.023 · 5175.024 · 5176.025 · 5177.026 · MV-4-11.003 · iso.002 · no Ab.001 · ACK 5150.003 · ACK 5151.004 · ACK 5152.005 · ACK 5153.006 · ACK 5154.007 · ACK 5155.008 · ACK 5156.009 · ACK 5158.010 · ACK 5159.011 · ACK 5160.012 · ACK 5162.013 · ACK 5163.014 · ACK 5164.015 · ACK 5165.016 · ACK 5166.017 · ACK 5167.018 · ACK 5170.019 · ACK 5171.020 · ACK 5173.021 · ACK 5174.022 · ACK 5175.023 · ACK 5176.024 · ACK 5177.025 · Beads 5150.026 · Beads 5151.027 · Beads 5152.028 · Beads 5155.029 · Beads 5156.030 · Beads 5158.031 · Beads 5159.032 · Beads 5160.033 · Beads 5163.034 · Beads 5165.035 · Beads 5166.036 · Beads 5167.037 · Beads 5170.038 · Beads 5171.039 · Beads 5173.040 · Beads 5174.041 · Beads 5175.042 · Beads 5176.043 · Beads 5177.044 · MNC POS.002 · beads only.001 · HLA-ABC BM 5159.006 · HLA-ABC BM 5164.005 · HLA-ABC PB 5159.002 · HLA-ABC PB 5164.001 · HLA-ABC SPL 5159.004 · HLA-ABC SPL 5164.003 · ISOTYPE BM 5159.012 · ISOTYPE BM 5164.011 · ISOTYPE PB 5159.008 · ISOTYPE PB 5164.007 · ISOTYPE SPL 5159.010 · ISOTYPE SPL 5164.009 · TB HLA-ABC BM 5159.018 · TB HLA-ABC BM 5164.017 · TB HLA-ABC PB 5159.014 · TB HLA-ABC PB 5164.013 · TB HLA-ABC SPL 5159.016 · TB HLA-ABC SPL 5164.015 · TB ISOTYPE BM 5159.024 · TB ISOTYPE BM 5164.023 · TB ISOTYPE PB 5159.020 · TB ISOTYPE PB 5164.019 · TB ISOTYPE SPL 5159.022 · TB ISOTYPE SPL 5164.021 · APOP 5154 BM ABC.013 · APOP 5154 BM ISO.025 · APOP 5154 PB ABC.005 · APOP 5154 PB ISO.017 · APOP 5154 SPL ABC.009 · APOP 5154 SPL ISO.021 · APOP 5171 BM ABC.012 · APOP 5171 BM ISO.024 · APOP 5171 PB ABC.004 · APOP 5171 PB ISO.016 · APOP 5171 SPL ABC.008 · APOP 5171 SPL ISO.020 · APOP 5175 BM ABC.015 · APOP 5175 BM ISO.027 · APOP 5175 PB ABC.007 · APOP 5175 PB ISO.019 · APOP 5175 SPL ABC.011 · APOP 5175 SPL ISO.023 · APOP 5176 BM ABC.014 · APOP 5176 BM ISO.026 · APOP 5176 PB ABC.006 · APOP 5176 PB ISO.018 · APOP 5176 SPL ABC.010 · APOP 5176 SPL ISO.022 · MV-4-11 ABC.003 · MV-4-11 no Ab.001 · MV-4-11 no isotype.002 · TB 5154 BM ABC.037 · TB 5154 BM ISO.049 · TB 5154 PB ABC.029 · TB 5154 PB ISO.041 · TB 5154 SPL ABC.033 · TB 5154 SPL ISO.045 · TB 5171 BM ABC.036 · TB 5171 BM ISO.048 · TB 5171 PB ABC.028 · TB 5171 PB ISO.040 · TB 5171 SPL ABC.032 · TB 5171 SPL ISO.044 · TB 5175 BM ABC.039 · TB 5175 BM ISO.051 · TB 5175 PB ABC.031 · TB 5175 PB ISO.043 · TB 5175 SPL ABC.035 · TB 5175 SPL ISO.047 · TB 5176 BM ABC.038 · TB 5176 BM ISO.050 · TB 5176 PB ABC.030 · TB 5176 PB ISO.042 · TB 5176 SPL ABC.034 · TB 5176 SPL ISO.046 · BM 5155 ISO.025 · BM 5160 ISO.024 · PB 5155 ISO.022 · PB 5160 ISO.023 · SPL 5155 ISO.027 · SPL 5160 ISO.026 · APOP BM 5150.023 · APOP BM 5151.021 · APOP BM 5152.020 · APOP BM 5153.024 · APOP BM 5158.028 · APOP BM 5165.019 · APOP BM 5170.025 · APOP BM 5173.026 · APOP BM 5174.022 · APOP BM 5177.027 · APOP MV-4-11.018 · APOP PB 5150.043 · APOP PB 5151.041 · APOP PB 5152.040 · APOP PB 5153.044 · APOP PB 5158.045 · APOP PB 5165.039 · APOP PB 5174.042 · APOP SPL 5150.033 · APOP SPL 5151.031 · APOP SPL 5152.030 · APOP SPL 5153.034 · APOP SPL 5158.038 · APOP SPL 5165.029 · APOP SPL 5170.035 · APOP SPL 5173.036 · APOP SPL 5174.032 · APOP SPL 5177.037 · BM 5150.005 · BM 5151.003 · BM 5152.002 · BM 5153.006 · BM 5155 HLA-ABC .005 · BM 5158.009 · BM 5160 HLA-ABC .004 · BM 5165.001 · BM 5170.010 · BM 5173.011 · BM 5174.004 · BM 5177.012 · MV-4-11 POS.003 · MV-4-11 isotype.002 · NO-Ab.001 · PB 5150.017 · PB 5151.015 · PB 5152.014 · PB 5155 HLA-ABC .009 · PB 5158.001 · PB 5160 HLA-ABC .008 · PB 5165.013 · PB 5170.002 · PB 5173.003 · PB 5174.016 · PB 5177.004 · SPL 5150.011 · SPL 5151.009 · SPL 5152.008 · SPL 5153.012 · SPL 5155 HLA-ABC .007 · SPL 5158.005 · SPL 5160 HLA-ABC .006 · SPL 5165.007 · SPL 5170.006 · SPL 5173.007 · SPL 5174.010 · SPL 5177.008 · TB BM 5155 HLA-ABC .011 · TB BM 5155 ISO.017 · TB BM 5160 HLA-ABC .010 · TB BM 5160 ISO.016 · TB PB 5155 HLA-ABC .015 · TB PB 5155 ISO.021 · TB PB 5160 HLA-ABC .014 · TB PB 5160 ISO.020 · TB SPL 5155 HLA-ABC .013 · TB SPL 5155 ISO.018 · TB SPL 5160 HLA-ABC .012 · TB SPL 5160 ISO.019

Doses
· vehicle control HLA-ABC BM 5164.005 · HLA-ABC PB 5164.001 · HLA-ABC SPL 5164.003 · ISOTYPE BM 5164.011 · ISOTYPE PB 5164.007 · ISOTYPE SPL 5164.009 · TB HLA-ABC BM 5164.017 · TB HLA-ABC PB 5164.013 · TB HLA-ABC SPL 5164.015 · TB ISOTYPE BM 5164.023 · TB ISOTYPE PB 5164.019 · TB ISOTYPE SPL 5164.021 · APOP 5154 BM ABC.013 · APOP 5154 BM ISO.025 · APOP 5154 PB ABC.005 · APOP 5154 PB ISO.017 · APOP 5154 SPL ABC.009 · APOP 5154 SPL ISO.021 · APOP 5171 BM ABC.012 · APOP 5171 BM ISO.024 · APOP 5171 PB ABC.004 · APOP 5171 PB ISO.016 · APOP 5171 SPL ABC.008 · APOP 5171 SPL ISO.020 · TB 5154 BM ABC.037 · TB 5154 BM ISO.049 · TB 5154 PB ABC.029 · TB 5154 PB ISO.041 · TB 5154 SPL ABC.033 · TB 5154 SPL ISO.045 · TB 5171 BM ABC.036 · TB 5171 BM ISO.048 · TB 5171 PB ABC.028 · TB 5171 PB ISO.040 · TB 5171 SPL ABC.032 · TB 5171 SPL ISO.044 · BM 5160 ISO.024 · PB 5160 ISO.023 · SPL 5160 ISO.026 · APOP BM 5152.020 · APOP BM 5165.019 · APOP BM 5170.025 · APOP BM 5177.027 · APOP PB 5152.040 · APOP PB 5165.039 · APOP SPL 5152.030 · APOP SPL 5165.029 · APOP SPL 5170.035 · APOP SPL 5177.037 · BM 5152.002 · BM 5160 HLA-ABC .004 · BM 5165.001 · BM 5170.010 · BM 5177.012 · PB 5152.014 · PB 5160 HLA-ABC .008 · PB 5165.013 · PB 5170.002 · PB 5177.004 · SPL 5152.008 · SPL 5160 HLA-ABC .006 · SPL 5165.007 · SPL 5170.006 · SPL 5177.008 · TB BM 5160 HLA-ABC .010 · TB BM 5160 ISO.016 · TB PB 5160 HLA-ABC .014 · TB PB 5160 ISO.020 · TB SPL 5160 HLA-ABC .012 · TB SPL 5160 ISO.019
· I-BET151 HLA-ABC BM 5159.006 · HLA-ABC PB 5159.002 · HLA-ABC SPL 5159.004 · ISOTYPE BM 5159.012 · ISOTYPE PB 5159.008 · ISOTYPE SPL 5159.010 · TB HLA-ABC BM 5159.018 · TB HLA-ABC PB 5159.014 · TB HLA-ABC SPL 5159.016 · TB ISOTYPE BM 5159.024 · TB ISOTYPE PB 5159.020 · TB ISOTYPE SPL 5159.022 · APOP 5175 BM ABC.015 · APOP 5175 BM ISO.027 · APOP 5175 PB ABC.007 · APOP 5175 PB ISO.019 · APOP 5175 SPL ABC.011 · APOP 5175 SPL ISO.023 · APOP 5176 BM ABC.014 · APOP 5176 BM ISO.026 · APOP 5176 PB ABC.006 · APOP 5176 PB ISO.018 · APOP 5176 SPL ABC.010 · APOP 5176 SPL ISO.022 · TB 5175 BM ABC.039 · TB 5175 BM ISO.051 · TB 5175 PB ABC.031 · TB 5175 PB ISO.043 · TB 5175 SPL ABC.035 · TB 5175 SPL ISO.047 · TB 5176 BM ABC.038 · TB 5176 BM ISO.050 · TB 5176 PB ABC.030 · TB 5176 PB ISO.042 · TB 5176 SPL ABC.034 · TB 5176 SPL ISO.046 · BM 5155 ISO.025 · PB 5155 ISO.022 · SPL 5155 ISO.027 · APOP BM 5150.023 · APOP BM 5151.021 · APOP BM 5153.024 · APOP BM 5158.028 · APOP BM 5173.026 · APOP BM 5174.022 · APOP PB 5150.043 · APOP PB 5151.041 · APOP PB 5153.044 · APOP PB 5158.045 · APOP PB 5174.042 · APOP SPL 5150.033 · APOP SPL 5151.031 · APOP SPL 5153.034 · APOP SPL 5158.038 · APOP SPL 5173.036 · APOP SPL 5174.032 · BM 5150.005 · BM 5151.003 · BM 5153.006 · BM 5155 HLA-ABC .005 · BM 5158.009 · BM 5173.011 · BM 5174.004 · PB 5150.017 · PB 5151.015 · PB 5155 HLA-ABC .009 · PB 5158.001 · PB 5173.003 · PB 5174.016 · SPL 5150.011 · SPL 5151.009 · SPL 5153.012 · SPL 5155 HLA-ABC .007 · SPL 5158.005 · SPL 5173.007 · SPL 5174.010 · TB BM 5155 HLA-ABC .011 · TB BM 5155 ISO.017 · TB PB 5155 HLA-ABC .015 · TB PB 5155 ISO.021 · TB SPL 5155 HLA-ABC .013 · TB SPL 5155 ISO.018

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