Study Findings Eliminate BCL-W as a Therapeutic Target for B-Cell Lymphomas

In a study published in Blood Advances, researchers at the Walter and Eliza Hall Institute have eliminated the BCL-W protein from the list of proteins important to the sustained growth and survival of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) cell lines.¹

Given this finding, targeting BCL-W in these types of B-cell lymphomas might not offer immense therapeutic benefit. 

“It is likely that other pro-survival proteins are much more important in these diseases,” study author Gemma L. Kelly, BSc, PhD, said in a press release.²

Recent studies have shown that BCL-W has been abnormally upregulated in BL, DLBCL, and Hodgkin lymphoma patient samples, suggesting that this protein could promote cancer cell survival. Additionally, it has also been previously reported that loss of BCL-W delays lymphoma development in the Eμ-Myc transgenic mouse model of BL and, importantly, that BCL-W expression is crucial for the continued survival of MYC-driven human BL-derived cell lines. Moreover, a CRISPR/CAS9 functional screen established BCL-W as a factor rendering a range of human adenocarcinoma-derived cell lines resistant to BH3-mimetic drugs targeting BCL-2, MCL-1 or BCL-XL.

Sarah T. Diepstraten, BSc, PhD, also an author of the study, said this is what inspired their research. “This led to speculation that drugs targeting BCL-W could be useful for treating B-cell lymphomas,” she said in a press release. 

To determine if BCL-W would be a prospective therapeutic target for B-cell lymphomas, researchers looked at the role of BCL-W in the sustained growth of human BL-and DLBCL-derived cell lines. In doing so, they found that CRISPR/CAS0-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a variation of BH3-mimetic drugs targeting other BCL-2 pro-survival proteins. 

“We also investigated the possibility that high levels of BCL-W in lymphomas might cooperate with other related survival proteins, such as BCL-2 or MCL-1, to promote survival,” Diepstraten said. “However, this was not the case: loss of BCL-W did not sensitize lymphoma cells to drugs that inhibit BCL-2 or MCL-1.”

Notably though, the researchers indicated that it is still possible that BCL-W may play a role in the development of B-cell lymphomas and could be an effective therapeutic target for other human malignancies that were not observed in the current study.

“BCL-W is considered to be a particularly appealing therapeutic target because it is not required for the function of most normal (non-cancerous) cells in the body, so we would not expect drugs targeting BCL-W to have significant side effects,” Kelly said. “While BCL-W may not be a critical survival factor for B-cell lymphomas, it is possible that BCL-W may contribute to the survival or drug resistance of other types of cancer – meaning that BCL-W inhibitors could be relevant in these cases.” 

References:

1. Diepstraten ST, Chang C, Tai L, et al. BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines. Blood Advances. Doi:10.1182/bloodadvances.2019000541.

2. Suspect eliminated as a therapeutic target in B cell lymphoma [news release]. Walter and Eliza Hall Institute. Published February 4, 2020. eurekalert.org/pub_releases/2020-02/waeh-sea020420.php. Accessed February 6, 2020.