Decreased BIM expression in BCL2-negative follicular lymphoma: a potential mechanism for resistance to apoptosis

Abstract

Follicular lymphoma (FL) is characterized by t(14; 18)(q32; q21), leading to overexpression of the antiapoptotic molecule BCL2; however, a subset of FLs lack BCL2 rearrangement and BCL2 expression as analyzed by immunohistochemistry (IHC). In this study, we evaluated expression of antiapoptotic (MCL1 and BCL-XL) and proapoptotic proteins (BIM) by IHC in both BCL2(-) and BCL2(+) FLs. FLs diagnosed between 2009 and 2019 were reviewed to identify BCL2(-) cases by IHC (assessed by clone 124). Immunohistochemical analyses for BCL2 (EP36), MCL1, BIM, BCL-XL, and Ki-67 were performed on tissue microarrays or whole slides. BCL2 (EP36) was interpreted as positive (≥10%) or negative (<10%). Ki-67 was interpreted on tumor cells in 10% increments. The remaining immunohistochemical analysis results were scored on tumor cells in 10% increments, and intensity was interpreted as weak, moderate, or strong to derive an H-score. Twenty-four BCL2(-) FLs were initially identified, but on further testing with BCL2(EP36) immunohistochemical staining, 5 of 24 were reclassified as BCL2(+), leaving 19 BCL2(-) FLs. Thirty-three BCL2(+) FLs were selected with sufficient tissue for additional immunohistochemical analyses. There was no significant difference in expression of antiapoptotic BCL-XL or MCL1 between BCL2(-) and BCL2(+) FLs (p=0.75 and 0.28, respectively). However, proapoptotic BIM expression was significantly lower in BCL2(-) FLs than in BCL2(+) FLs (p=0.002). In our study, 21% of putative BCL2(-) FLs were BCL2(+) when tested with alternative clones, supporting the practice of having more than one BCL2 clone in immunohistochemical laboratories. Decreased BIM expression in BCL2(-) FLs could have an overall antiapoptotic effect and represent an alternate mechanism for cell survival in BCL2(-) FLs.