Mitigating the BFL1-mediated antiapoptotic pathway in diffuse large B cell lymphoma by inhibiting HDACs

Abstract

Endogenous BFL1 expression renders diffuse large B-cell lymphoma (DLBCL) cells insensitive to B-cell lymphoma 2 (BCL2) and/or MCL1 inhibitors. Considering the difficulties in developing a direct BFL1 inhibitor, we intended to inhibit histone deacetylase (HDAC) to mitigate the biological role of BFL1 by modulating WT1 and NOXA. Cells expressing high BFL1 exhibited enhanced sensitivity to pan-HDAC inhibitor compared to low BFL1 expressing cells, mainly attributable to the difference in the amount of apoptosis. HDAC inhibitors decreased BFL1 and WT1 expressions while increasing NOXA levels. The BFL1 knockdown experiment demonstrated that HDAC inhibitor’s sensitivity depends on the BFL1 expression in DLBCL cells. Furthermore, we found that the specific HDAC class was expected to play a critical role in BFL1 inhibition by comparing the effects of several HDAC inhibitors. Thus, our study provides a rationale for using HDAC inhibitors to induce apoptosis in DLBCL patients using BFL1 as a predictive biomarker.

Keywords:

• Diffuse large B-cell lymphoma (DLBCL)
• BFL1
• histone deacetylase (HDAC) inhibitor
• response prediction
• biomarker
• apoptosis

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are openly available in NCBI at https://www.ncbi.nlm.nih.gov/sra, reference number PRJNA806671.

Additional information

Funding

This work was supported by the Korea Health Industry Development Institute (KHIDI) under Grant No. HI14C1277 and National Research Foundation of Korea (NRF) under Grant No. 2021R1A2C3005360.