Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice

Lee, Dong U.; Katavolos, Paula; Palanisamy, Gopinath S.; Katewa, Arna; Sioson, Charly; Corpuz, Janice; Pang, Jodie; DeMent, Kevin; Choo, Edna F.; Ghilardi, Nico; Dı́az, Dolores; Danilenko, Dimitry M.

doi:10.1016/j.taap.2016.03.013

Cited by 35 publications

(45 citation statements)

References 27 publications

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“…In addition to efficacy, the nonclinical safety of BET inhibition has also been examined. In mesenchymal stem cells, (+)-JQ1 was reported to induce cell cycle arrest and downregulation of genes involved in self-renewal, mitosis, and DNA replication (Alghamdi et al, 2016), while mice treated with (+)-JQ1 at an efficacious dose resulted in lymphoid and hematopoietic toxicity (Lee et al, 2016). Currently, several BET bromodomain inhibitors, with slight variation in mechanism, are in clinical trials for patients with various hematologic and solid malignancies (Chaidos et al, 2015; French, 2016; Wadhwa and Nicolaides, 2016).…”

Section: Introductionmentioning

confidence: 99%

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

Aird

Kandela

Mantis

2017

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.21253.001

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Section: Introductionmentioning

confidence: 99%

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

Aird

Kandela

Mantis

2017

eLife

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“…The general tolerability of JQ1 at the doses used here is further supported by our observation that mice receiving daily JQ1 injections are able to complete a high-intensity, 4-week swimming protocol. However, higher doses of BET inhibitors will bring broader, sustained exposure that may produce a wider range of on-target toxicity (57, 58). A mouse model in which total BRD4 protein abundance is ubiquitously suppressed by an inducible short hairpin RNA (shRNA) demonstrates that excessive levels of total BRD4 depletion result in abnormalities in the intestinal epithelium, bone marrow, and hair follicles—all of which are reversible after the shRNA expression is turned off (56).…”

Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

et al. 2017

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Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

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“…These proteins help link promoters and enhancers to facilitate transcriptional initiation and elongation. Inhibitors of the bromodomain protein BRD4 (BET), lead to the downregulation of MYC and its target genes critical for the development of MM (108) (109, 110). The upregulation of MYC , is seen in up to 50% of MM and it has been associated with the development of MM from MGUS, as well as late disease progression (111).…”

Section: Drugs Targeting Histone Acetylationmentioning

confidence: 99%

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

Dupéré-Richér

Licht

2017

Current Opinion in Hematology

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Purpose of review Next generation sequencing and large scale analysis of patient specimens has created a more complete picture of Multiple Myeloma (MM) revealing that epigenetic deregulation is a prominent factor in MM pathogenesis. Recent findings Over half of MM patients have mutations in genes encoding epigenetic modifier enzymes. The DNA methylation profile of MM is related to the stage of the disease and certain classes of mutations in epigenetic modifiers are more prevalent upon disease relapse, suggesting a role in disease progression. Many small molecules targeting regulators of epigenetic machinery have been developed and clinical trials are underway for some of these in MM. Summary Recent findings suggest that epigenetic targeting drugs could be an important strategy to cure MM. Combining these agents along with other strategies to affect the MM cell such as IMIDs and proteasome inhibitors may enhance efficacy of combination regimens in MM.

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Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice

Cited by 35 publications

References 27 publications

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

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

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

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