Expression of NFATc1 in Diffuse Large B Cell Lymphomas (DLBCL) Is Decreased in HIV Positive Patients

Background: DLBCL is the most common non-Hodgkin lymphoma (NHL), comprising 30 to 40% of adult NHLs. It may present with nodal or extranodal involvement or it may be primary to the central nervous system (CNS). HIV positive patients comprise a significant percentage of patients diagnosed with DLBCL, however, differences in molecular characteristics based on HIV status have not been elucidated. Understanding the molecular basis for lymphomas is integral to the development of targeted therapy. The NFAT (nuclear factor of activated T cells) family is a group of cytoplasmic transcription factors that undergoes nuclear translocation when activated and plays an important role in intracellular signaling. This study evaluated the differential expression of the NFATc1 protein in HIV positive and negative patients with DLBCL (nodal, extranodal and primary CNS).

Design: Formalin-fixed, paraffin-embedded archival tissue from 34 nodal/extranodal DLBCLs and 41 primary CNS DLBCLs were immunostained with antibodies against NFATc1 by automated methods (NFATc1 (7A6):sc-7294, Santa Cruz Biotechnology, Inc, Santa Cruz, CA;Ventana Medical Systems, Inc, Tucson, AZ). Nuclear immunoreactivity in neoplastic tissue was semiquantitatively assessed and the results were correlated with HIV status and overall patient survival.

Results: Nuclear NFATc1 immunoreactivity was noted in both nodal/extranodal and primary CNS DLBCLs with 13/34 (38%) nodal/extranodal DLBCLs and 13/41 (32%) primary CNS DLBCLs showing nuclear NFAT1c positivity. Of the 59 total HIV negative cases, 42% (25/59) showed nuclear NFAT1c immunoreactivity. In contrast, less than 1% (1/16) of HIV positive cases demonstrated nuclear NFAT1c immunoreactivity (p=0.007). Within the nodal/extranodal DLBCL subgroup, nuclear NFATc1 positivity was observed in 12/23 (52%) HIV negative cases versus 1/11 (9%) HIV positive cases; while within the primary CNS subgroup nuclear positivity was noted in 13/36(36%) HIV negative cases versus 0/5(0%) HIV positive cases. There was no correlation with overall survival in either subgroup.

Conclusions: Similar to previous studies, nuclear NFAT1c immunoreactivity was demonstrated in DLBCLs and primary CNS lymphomas. Interestingly, this nuclear NFAT1c immunoreactivity was significantly decreased among patients with HIV positive status suggesting activation of alternative intracellular signaling pathways. These findings highlight potential variations in gene expression among DLBCLs based on HIV status. This decreased expression of NFAT1c amongst HIV positive individuals may be of particular importance when developing targeted therapy for aggressive B-cell malignancies.