Abstract
BackgroundIndividuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined.Methodology/Principal FindingsWe used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis.ConclusionDysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.
Highlights
The risk for developing non-Hodgkin lymphoma (NHL) is greatly increased in those persons who are living with HIV infection
Ethics statement An application for the use of all anonymized patient samples, including tonsils, peripheral blood, and archived tissues utilized in this study was submitted to the University of California Los Angeles (UCLA) Institutional Review Board (IRB), which concluded that these activities did not involve human subjects, and did not require IRB review or certification, or exemption from IRB review
Tonsillar B cell subsets show a remarkable level of coregulation of miRNAs as groups in an asymmetrical fashion, especially that of the miR-17-92 paralog clusters, which is germinal center (GC) subset specific
Summary
The risk for developing non-Hodgkin lymphoma (NHL) is greatly increased in those persons who are living with HIV infection. NHL in the setting of HIV infection, is an AIDS defining condition. In the post-HAART era there has been a dramatic reduction in the incidence of PCNSL, only a modest decrease has been reported for other NHL subtypes [2,3]. Individuals infected by HIV are at an increased risk for developing non-Hodgkin’s lymphomas (AIDS-NHL). AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. The role of miRNAs in NHL in the setting of HIV infection has not been defined
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