Page 17 - Haematologica June

Ludovica Marando1,2,3 and Brian J. P. Huntly1,2,3
1Wellcome Trust‐MRC Cambridge Stem Cell Institute; 2Department of Haematology, University of Cambridge and 3Cambridge Institute for Medical Research, Cambridge Biomedical Campus, UK
haematologica | 2018; 103(6)
mediated by JQ1 dependant suppression of Myb,18 given the phenotypic similarity between JQ1 treatment and a mouse
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to sustained target inhibition, and due to its limited efficacy in pre-clinical models, JQ1 has never been tested in clinical trials.20 Therefore, whether JQ1 induced expansion of the normal HSC pool described here is a “class effect” shared by more potent BET inhibitors needs to be carefully addressed by further studies. This is further called into question by the toxicity reports from the clinical trials that have consistently reported hematologic toxicity, in particular, a dose-depen- dent, non-cumulative, reversible thrombocytopenia,10,11 and by opposing reports in the literature regarding the effects of BET inhibition on normal HSC. In a mouse model of con- trolled BRD4 inhibition, using an inducible transgenic shRNA, Brd4 silencing caused a significant reduction in Lineage- Sca-1+ c-kit+ hematopoietic stem cells 12 weeks after hematopoietic reconstitution.21 However, as RNAi would not only lead to almost complete loss of Brd4, but would also target the non-bromodomain dependent func- tions of the protein, differences between these models, where inhibitors would only intermittently target the bro- modomains, might be expected.
Certainly the possibility that BET inhibitors, in addition to exerting antitumor effects, could enhance recovery of nor- mal hematopoiesis, especially after combination chemother- apy, is intriguing and could open up new avenues for the use of BET inhibitors in clinical practice (Figure 1). Other areas of utility for BET inhibition, as suggested by Wroblewski et al.,17 could include mobilization of peripheral blood (PB) HSC from donors who fail more standard approaches. However, validation of this study with orally available BET inhibitors and specific testing of these hypotheses will be necessary.
BET inhibitors might also have a role against acute graft- versus-host disease (GvHD) and, in fact, were initially designed as immunosuppressives. Wroblewski et al.17 and others have shown that BET inhibitors impair T-cell func- tion. Specifically, Wroblewski et al.17 find that JQ1 treatment causes increased apoptosis in T cells, and this is associated with reduced expression of the antiapoptotic BCL-2 as meas- ured by RT-qPCR. Others have demonstrated that treatment with I-BET151 results in a reduction in the secretion of IL-6, TNF-α, and IL-12 by stimulated dendritic cells (DCs).22 Both T cells and DCs are important mediators of GvHD in recipi- ents of allogeneic stem cell transplant, suggesting that BET inhibitors may serve as a prophylactic therapy against acute GvHD. Again, the results suggested by the pre-clinical mod- els need to be validated in clinical trials and the benefits must be weighed against the risks of hematologic toxicity, partic- ularly thrombocytopenia and neutropenia.
In conclusion, BRD4/BET inhibition is becoming a novel
model of reduced Myb activity.
Due to its pharmacokinetic properties, JQ1 does not lead
EDITORIALS
Hematopoietic stem cells made BETter by inhibition
E-mail: bjph2@cam.ac.uk doi:10.3324/haematol.2018.193706
Bromodomain and extra terminal (BET) proteins com- prise the ubiquitously expressed BRD2, BRD3, BRD4
1,2
and the testes specific BRDT. These multipurpose pro-
teins contain tandem N-terminal bromodomains that bind acetylated lysine residues of histone (and non-histone) pro- teins and other protein modules, such as the extra terminal domain, and in some (BRD4, BRDT), a C-terminal domain. They also mediate a number of effects including transcription- al activation via recruitment of other partner proteins.3 Inhibitors of these proteins are emerging as exciting new ther- apies for the treatment of hematologic and solid malignancies, offering the possibility of specifically targeting epigenetic readers. We and others have already demonstrated the pre- clinical efficacy of BET inhibitors in acute myeloid leukemia (AML),4-6 while several other papers have documented similar efficacy in myeloma,7 non-Hodgkin lymphoma,8 and acute lymphoblastic leukemia.9 These observations have led to sev- eral clinical trials that are currently underway to confirm the efficacy of these drugs in AML and other malignancies. Even though the most mature trials have recently reported limited objective responses of monotherapy in heavily pre-treated AML, lymphoma and myeloma patients,10-12 early data suggest that combination therapies with other small molecules or more conventional cytotoxic agents might be particularly promising.13-15
BET proteins have multiple functions. Amongst these, and considered critical for the maintenance of malignant tran- scription, they are implicated in the regulation of large or “super” enhancers that control a number of critical genes, including oncogenes pivotal for the maintenance of leukemia, such as BCL-2, IRF8, and c-MYC. Their downreg- ulation upon treatment with small molecule BET inhibitors at least partially explains the effects of BET inhibition observed in hematologic and solid malignancies.4,13,15,16
However, despite several ongoing clinical trials, we know surprisingly little about the consequences of disrupting BET protein function in normal tissues. In this issue of the Journal, Wroblewski et al.,17 therefore, address a highly rele- vant topic and describe the effects of the prototypic BET inhibitor JQ1 on normal hematopoiesis.
Surprisingly, upon JQ1 treatment, Wroblewski et al. identi- fy an increase in phenotypic HSC proliferation and mobiliza- tion in mice. In addition, these effects seem sustained, and functionally, in the setting of competitive transplantation, JQ1 treated HSC appear to contribute more to hematopoiesis in primary and, importantly, in secondary recipients with no evidence of exhaustion, albeit follow up was only for 12 months following transplantation. This increased proliferation does not enhance radiosensitivity. On the contrary, JQ1 treated mice show faster count recovery following sublethal irradiation compared to untreated con- trols. Although the authors have not studied potential under- lying mechanisms, they postulate that the effects might be
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