BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines

Abstract

Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1–targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit.

Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma

“…Overexpression of BCLW has been observed in DLBCL cell lines and has been associated with resistance to apoptosis and decreased patient survival [ 54 , 55 ]. However, these results have not been observed in a recent study [ 56 ]. Overall, there are no notable genetic alteration in BCLX and BCLW in DLBCL, and the role of the proteins encoded by these two genes is minor in comparison to BCL2 and MCL1 [ 44 ].…”

BCL-w: apoptotic and non-apoptotic role in health and disease

“…In another report, however, BCL-w was expressed at high level only in a subset of BL and DLBCL cell lines. Moreover, CRISPR/ CAS9 gene editing or RNA interference leading to downregulation of BCL2L2 expression did not sensitize lymphoma cells to apoptosis, even when these cells were exposed to BH3 mimetics 134 . It has been also demonstrated that BCL-w, in addition to BCL-2 and BCL-X L , played a minor role in the development of sarcoma and thymic lymphoma in p53-deficient mice 135 .…”

“…The contribution of BCL-w to differentiation of lymphocytes has appeared questionable as BCL2L2-knockout mice exhibited unaffected lymphoid development 55 , probably as a result of low level of BCL-w in normal and malignant lymphoid cells 26 . Further research is necessary to determine an unequivocal role of BCL-w in these cells in the light of conflicting results of more recent reports 47,134 . Notably, the redundant role of BCL-w is in sharp contrast to other pro-survival members of the BCL-2 family that have been shown essential during embryogenesis, development of nervous system and hematopoiesis as exemplified especially by BCL-2, MCL-1 and BCL-X L 153-155 .…”

BH3 Mimetics in Hematologic Malignancies

“…However, increased expression of BCL-W is linked to tumorigenesis in various types of cancers [ 177 ]. Among hematologic malignancies, BCL-W is highly expressed in a subset of c-MYC-expressing DLBCL and Burkitt lymphomas as well as B-CLL cells, although it appears dispensable for their survival [ 176 , 178 ]. Thus far, no BCL-W-specific BH3 mimetics have been discovered, most likely due to its high conformational flexibility.…”