Epigenetic Targeting of Waldenström Macroglobulinemia Cells with Bet Inhibitors Synergizes with BCl2 or Histone Deacetylase Inhibition

Abstract

Aim: Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. To date, there are no therapies that provide a cure for WM patients, and therefore, it is important to explore new therapies. Little is known about the efficiency of epigenetic targeting in WM. Materials & methods: WM cells were treated with BET inhibitors (JQ1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. Results: BET inhibition reduces growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Conclusion: Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.

Keywords::

• BET inhibitors
• epigenetics
• panobinostat
• venetoclax
• Waldenström macroglobulinemia

Acknowledgments

The FACS Calibur used is managed by the University Instrumentation Center (UIC) at the University of New Hampshire (UNH) and was purchased by the UIC. The Tescan Lyra3 GMU field-emission scanning electron microscope/focused ion beam (FE-SEM/FIB) used is managed by the UIC at the UNH and was purchased with funds awarded to UNH from the US National Science Foundation (NSF) (MRI grant 1337897; T Gross, Mechanical Engineering, UNH, PI) and funds from UNH. EDS/EBSD components on this system were purchased with startup funds from UNH at the discretion of M Knezevic (Mechanical Engineering, UNH).

Financial & competing interests disclosure

This research was supported by an NIH COBRE Center of Integrated Biomedical and Bioengineering Research (CIBBR, P20 GM113131) through an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences. This work was supported in part by a grant from the International Waldenström Macroglobulinemia Foundation and the Leukemia & Lymphoma Society (IWMF-LLS). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was supported by an NIH COBRE Center of Integrated Biomedical and Bioengineering Research (CIBBR, P20 GM113131) through an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences. This work was supported in part by a grant from the International Waldenström Macroglobulinemia Foundation and the Leukemia & Lymphoma Society (IWMF-LLS). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.