Epigenetic targeting of Waldenström macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition

Stephan J Matissek; Weiguo Han; Mona Karbalivand; Mohamed Sayed; Brendan M Reilly; Shayna Mallat; Shimaa M Ghazal; Manit Munshi; Guang Yang; Steven P Treon; Sarah R Walker; Sherine F Elsawa

doi:10.2217/epi-2020-0189

Epigenetic targeting of Waldenström macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition

Epigenomics. 2021 Jan;13(2):129-144. doi: 10.2217/epi-2020-0189. Epub 2020 Dec 24.

Authors

Stephan J Matissek¹, Weiguo Han¹, Mona Karbalivand¹, Mohamed Sayed¹, Brendan M Reilly¹, Shayna Mallat¹, Shimaa M Ghazal¹, Manit Munshi^{2

3}, Guang Yang^{2

3}, Steven P Treon^{2

3}, Sarah R Walker¹, Sherine F Elsawa¹

Affiliations

¹ Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, 03824, USA.
² Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.

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; Waldenström macroglobulinemia; epigenetics; panobinostat; venetoclax.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenine / analogs & derivatives
Adenine / pharmacology
Antineoplastic Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Epigenesis, Genetic / drug effects*
Epigenesis, Genetic / genetics
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / genetics
Humans
Lymphoma, B-Cell / drug therapy
Lymphoma, B-Cell / genetics
Molecular Targeted Therapy / methods
Nerve Tissue Proteins / genetics*
Piperidines / pharmacology
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics*
Receptors, Cell Surface / genetics*
Sulfonamides / pharmacology
Waldenstrom Macroglobulinemia / drug therapy*
Waldenstrom Macroglobulinemia / genetics
Waldenstrom Macroglobulinemia / metabolism

Substances

Antineoplastic Agents
BCL2 protein, human
Bridged Bicyclo Compounds, Heterocyclic
DNER protein, human
Histone Deacetylase Inhibitors
Nerve Tissue Proteins
Piperidines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Receptors, Cell Surface
Sulfonamides
ibrutinib
Histone Deacetylases
Adenine
venetoclax

Grants and funding

P20 GM113131/GM/NIGMS NIH HHS/United States