BNIP3 expression in follicular lymphoma J Sington, A Giatromanolaki, L Campo, H Turley, F Pezzella & K C Gatter Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK Date of submission 19 April 2006 Accepted for publication 17 July 2006 Sington J, Giatromanolaki A, Campo L, Turley H, Pezzella F & Gatter K C (2007) Histopathology 50, 555–560 BNIP3 expression in follicular lymphoma Aims: To investigate the role of BNIP3, a 19-kDa interacting protein of the Bcl-2 family, alongside Bcl-2 in follicular lymphoma in comparison with reactive lymphoid hyperplasia. The results were compared with those from p53 and caspase-3 (apoptotic markers) and Ki67 (proliferation marker). Methods and results: Immunohistochemistry using mono- clonal antibodies showed BNIP3 to be strongly ex- pressed in most follicular lymphomas but to be weak to negative in all of the reactive cases. There was also an inverse relationship with Bcl-2 expression. There was no correlation of BNIP3 immunoreactivity with proliferation and caspase and p53 were virtually negat- ive in all follicular lymphomas and reactive lymphoid cases. Conclusions: BNIP3 is strongly expressed in most folli- cular lymphomas, especially those that are Bcl-2 negative. BNIP3 may serve as a marker of more aggressive behaviour in follicular lymphoma and be useful diagnostically in the distinction from reactive lymphadenitis. Keywords: Bcl-2, BNIP3, follicular lymphoma, reactive lymphadenopathy Abbreviations: BNIP, Bcl-2 and nineteen-kilodalton interacting protein; FDC, follicular dendritic cell; FL, follicular lymphoma; HIF, hypoxia inducible factor Introduction Follicular lymphomas (FLs) represent 20% of all malignant lymphomas in adults. 1 The t(14;18)- (q32;q21) translocation of the BCL2 gene to the immunoglobulin heavy-chain gene locus is an import- ant, though not an invariable, event in the develop- ment of FLs. 2 Being under the influence of the immunoglobulin gene enhancer, Bcl-2 protein is over- expressed in > 90% of indolent FLs. 3 However, in approximately 10% of such cases the Bcl-2 protein cannot be detected immunohistochemically, suggesting the existence of additional pathways related to other members of the Bcl protein family (Bcl-6, bad). 4 Recently, T cells and accessory cells have been impli- cated in the progression of FLs. 5–7 Mature follicular dendritic cells (FDCs) (expressing the complement receptors CD21 and CD35, the immunoglobulin recep- tor CD23 and high levels of CXCL13) are capable of supporting a dense T-cell infiltrate, which appears to be important in sustaining an indolent disease course. 8,9 It is possible that progression of FL to diffuse large B-cell lymphoma, a common fatal evolution of the disease, does not constitute a gradual process but rather represents two different pathways driving the disease to a rapid or decelerated evolution. 10 t(14;18) or equivalent translocations are common prelymphoma events, while secondary genetic alterations lead either to activated FDC ⁄ T-cell status and rapid progression or to a resting FDC ⁄ T-cell status and slow transformation. The role of BNIP3, a 19-kDa interacting protein of the Bcl-2 family, has not been investigated in lymph- omas. BNIP3 is a preapoptotic mitochondrial protein isolated through its interaction with Bcl-2 and the adenovirus E1B19kDa proteins. 11,12 BNIP3 activates caspase-independent necrosis-like cell death by opening the mitochondrial permeability transition pore. 13,14 Hypoxia increases BNIP3 mRNA levels and this response is under the direct control of the hypoxia Address for correspondence: Professor Kevin C Gatter, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, The John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9 DU, UK. e-mail: kevin.gatter@ndcls.ox.ac.uk J.S. and A.G. are joint first authors. Ó 2007 The Authors. Journal compilation Ó 2007 Blackwell Publishing Limited. Histopathology 2007, 50, 555–560. DOI: 10.1111/j.1365-2559.2007.02657.x