B-cell non-Hodgkin lymphoma (NHL) is among the ten most common malignancies. Survival rates range from very poor to over 90% and highly depend on the stage and subtype. Characteristic features of NHL are recurrent translocations juxtaposing an oncogene (e.g. MYC, BCL2) to the enhancers in the immunoglobulin heavy chain (IGH) locus. Survival and proliferation of many B-cell lymphomas depend on the expression of the translocated oncogene. Thus, targeting IGH enhancers as an anti-lymphoma treatment seems a promising strategy. Recently, a small molecule - 7-[[(4-methyl-2-pyridinyl)amino](2-pyridinyl)methyl]-8-quinolinol (compound 30666) was identified to decrease activity of the Eμ enhancer and reduce the expression of translocated oncogenes in multiple myeloma and some NHL cell lines (Dolloff, 2019). Here, we aimed to test the effect of compound 30666 in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) and shed light on its mechanism of action. We report that both IGH-translocation positive NHL cells as well as IGH-translocation negative B cells and non-B cell controls treated with compound 30666 exhibited consistent growth inhibition. A statistically significant increase in cell percentage in sub-G1 phase of cell cycle was observed, suggesting induction of apoptosis. Compound 30666 downregulated MYC levels in BL cell lines and altered IGH enhancer RNA expression. Moreover, a global decrease of H3K27ac and an increase of H3K4me1 was observed upon 30666 treatment, which suggests switching enhancers to a poised or primed state. Altogether, our findings indicate that 30666 inhibitor affects enhancer activity but might not be as specific for IGH enhancers as previously reported.
Keywords: BCL2; Enhancer; IGH translocation; MYC; Non-Hodgkin lymphoma; eRNA.
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.