The lncRNA LINC02446 promotes tumor progression and HLH occurrence by regulating the expression of KLRs and IL-10 in EBV-NK-LPDs

Refractory Epstein-Barr virus-associated NK-cell lymphoproliferative diseases (EBV-NK-LPDs) are prone to hemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Although various therapies have been used to relieve the symptoms, hematopoietic stem cell transplantation is considered the only potentially therapeutic approach. There is an urgent need to explore the pathogenesis of EBV-NK-LPDs and develop an effective better treatment. Here, we investigated long non-coding RNA (lncRNA) profile using high-throughput RNA sequencing data (n = 6, healthy donors; n = 5, infectious mononucleosis; n = 10, chronic active Epstein-Barr virus disease (CAEBV)-NK; n = 7, CAEBV-T) and screened out LINC02446, whose upregulation was further validated by quantitative real-time polymerase chain reaction in EBV-NK-LPDs. We further explored the correlation between LINC02446 and the clinical characteristics of patients with EBV-NK-LPDs. Then, based on sequencing data, we performed in vitro experiments to investigate the function and mechanism of LINC02446 in EBV-NK-LPDs. LINC02446 was specifically highly expressed in NK cells of EBV-NK-LPDs patients. EBV-NK-LPDs patients with high expression of LINC02446 showed higher EBV-DNA copy number and ferritin levels, as well as a higher incidence of HLH. LINC02446 was closely related to the KLRs family and LINC02446 could regulate the expression of KLRs genes. In addition, LINC02446 positively regulated the expression of IL-10 in EBV-NK-LPDs cell lines, which revealed that LINC02446 may promote HLH by upregulating IL-10 in EBV-NK-LPDs. This is the first study that LINC02446 regulates the expression of KLRs family and IL-10 in EBV-NK-LPDs, resulting in lymphoma progression and HLH occurrence, showing its potential as a therapeutic target for EBV-NK-LPDs.