Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma

Venetoclax, anti-apoptotic BCL2-selective inhibitor, has demonstrated efficacy in B-cell multiple lymphoid malignancies. However, several studies have shown that the other anti-apoptotic BCL2 family genes can increase the risk of venetoclax resistance. Accordingly, compounds targeting other BCL2 family are actively being developed. So it is necessary to find which BCL2 family genes is overexpressed in certain tumors. We profiled BCL2 family genes expression with RNA-seq across different types of lymphoid malignancies (follicular lymphoma, burkitt lymphoma, diffuse large b-cell lymphoma, multiple myeloma, and acute leukocyte leukemia). Log2-transformed TMM-normalized RPKM was used for expression levels. As is known, BCL2 and MCL1 was highly expressed in follicular lymphoma and multiple myeloma, respectively. Interestingly, we discovered BFL1, one of anti-apoptotic BCL2 family genes, is overexpressed in both activated B-cell (ABC) and germinal center B-cell (GCB) type diffuse large B cell lymphoma (DLBCL). It has been well known that BFL1 is a pro-survival NF-kB target gene and indeed NF-kB pathway is highly activated in ABC-DLBCL. Also recent studies have shown that activation of this pathway can occur in GCB-DLBCL. Using gene set enrichment analysis, we confirmed that high expression of BFL1 is associated with negative regulation of intrinsic apoptosis and activation of NF-kB in B-cell. Also we discovered that NF-kB pathway activation in correlation with BFL-1 is especially dominant in DLBCL compared to other lymphoid malignancies. Among NF-kB signal related molecules (TNF receptors or Toll-like receptors), CD40 expression significantly correlated with BFL1 expression. In contrast, BCL2, another important apoptosis related gene, showed a negative association with the NF-kB pathway in DLBCL. We could validate our observation using microarray data. In conclusion, BFL1, which may controls intrinsic apoptosis and have strong correlation with NF-kB, is overexpressed in DLCBL. We suggest not venetoclax but BFL1 inhibitor may exert clinical benefit in DLBCL. Citation Format: Chansub Lee, Hyojin Song, Seulki Song, Daeyoon Kim, Jihyun Park, Sungyoung Lee, Hongseok Yun, Sheehyun Kim, Sung-Soo Yoon, Youngil Koh. Not BCL2 but BFL1 is overexpressed and have strong correlation with NF-kB pathway in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1248.