Page 18 - Haematologica June

Editorials
Figure 1. Effects of BET inhibition on normal and dis- eased hematopoiesis. Hematopoiesis is a finely regu- lated process precisely balancing hematopoietic stem cell (HSC) self-renewal and differentiation. In a pre- clinical model, BET inhibition seems to affect this tightly regulated mechanism, resulting (as shown) in increased HSC self-renewal and mobilization but also altered lymphocyte differentiation. Advantageous effects may occur on mobilization of peripheral blood HSC donors or could enhance restoration of normal hematopoiesis after chemotherapy through effects on normal HSC and by altering the balance between nor- mal and leukemic stem cells (LSCs). However, caution is required due to the demonstrated emergence of resistance within the leukemia stem cell compart- ment under sustained BET inhibition in recent pre- clinical models.
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and exciting treatment option in many hematologic and solid malignancies, and may have novel promising effects in bone marrow transplantation. However, little is known about the effects of such treatment in normal tissues and an ongoing concern has been about the size of the thera- peutic window. However, some reassurances are provided by the studies performed by Wroblewski et al. that have addressed this issue and suggest potentially beneficial effects on normal hematopoiesis; further studies are war- ranted to validate and extend these findings. However, a note of potential caution comes from models of BET inhibitor resistance that suggest that under the continuous and sustained selective pressures of BET inhibition, a small proportion of leukemic stem cells (LSC) survive and that over time these cells become the dominant clone. Mechanistically, this appears to occur through the activa- tion of the ancillary WNT/β-Catenin pathway that allows escape from BET inhibition. Importantly, resistance to BET inhibition in this model is only partially reversible on sus- pending I-BET.23 The evidence from the Fong et al. study,23 coupled with the evidence emerging from clinical trials and
early study of combination therapy, strengthens the argu- ment for developing rational combination strategies of BET inhibitors and other agents for patients with hematologic and solid malignancies. The Wroblewski et al. study17 promises an unexpected but welcome positive effect on normal hematopoiesis.
References
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2. Pivot-Pajot C, Caron C, Govin J, Vion A, Rousseaux S, Khochbin S. Acetylation-dependent chromatin reorganization by BRDT: a testis- specific bromodomain-containing protein. Mol Cell Biol. 2003;23(15): 5354-5365.
3. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin- binding modules interpret histone modifica- tions: lessons from profes- sional pocket pickers. Nat Struct Mol Biol. 2007;14(11):1025-1040.
4. DawsonMA,GudginEJ,HortonSJ,etal.Recurrentmutations:includ- ing NPM1c, activate a BRD4- dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2):311-320.
5 Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruit- ment to chromatine as an effective treatment for MLL fusion
haematologica | 2018; 103(6)