An Exploratory Study On The Treatment Of Chronic Active EB Virus Infection

Epstein-Barr virus, a pro-lymphoproliferative virus, is believed to be the real instigator of certain malignancies(i.e. lymphoma, nasopharyngeal carcinoma). Chronic active Epstein-Barr virus infection(CAEBV) represents a new subtype of lymphoproliferative disorders and is characterized by high morbidity/mortality rate and inclination of malignancies transformation. Up to now, effictive therapeutic strategies still remain undefined. The development of novel targeting agents is of highly importance in preventing its transformation and progression. Growing hidden information from clinical data(II/III latency, increased TNF-α, IL-1α and IL-1β levels and uncontrolled specific lymphocyte proliferation) makes us hypothesize that whether NF-κB is constitutively activated in CAEBV. If so, it appears to be a therapeutic target for such disease. Here, by using a series of celluar, molecular and bioinformatic methods, we have identified constitutively active NF-κB in CAEBV and that found NF-κB inhibitior(DHMEQ) can selectively target T-cell subtype CAEBV while sparing normal hematopoietic cell unaffected.Epstein-Barr virus, a pro-lymphoproliferative virus, is believed to be the real instigator of certain malignancies(i.e. lymphoma, nasopharyngeal carcinoma). Chronic active Epstein-Barr virus infection(CAEBV) represents a new subtype of lymphoproliferative disorders and is characterized by high morbidity and mortality and inclination of malignancies transformation. Up to now, efficient therapeutic strategies still remain undefined. Leading by Todd Golub and Eric Lander, they constitute the database Connectivity Map(C-MAP) by using human gene expression profiles treated with small molecule compounds. It is the first model to integrate gene expression profiling, small molecule compounds characteristics and disease biology. The database has been successfully applied to drug-screening in the field of leukemia stem cells, colon cancer and prostate cancer. To probe the possible candidate in CAEBV, we utilized the C-MAP database to forecast. In this study, we successfully identified that the histone deacetylase inhibitor-trichostatin A(TSA) is a compounds of great potential. TSA could enhance the cytotoxic effect of ganciclovir on CAEBV cells.Leukemia stem cells(LSCs) play important roles in disease initiation, progression and relapse, and represent a critical target for therapeutic intervention. However, relatively few agents have been shown to eliminate LSCs, slowing progress in the treatment of acute myelogenous leukemia(AML). We report here that fenretinide, a well-tolerated vitamin A derivative, is capable of eradicating LSCs but not normal hematopoietic progenitor/stem cells at physiologically achievable concentrations. We provided the evidence that fenretinide exerted a selective cytotoxic effect on primary AML CD34+ cells, especially the LSC-enriched CD34+CD38- subpopulation, whereas no significant effect was observed on normal counterparts. Methylcellulose colony formation assays further showed that fenretinide significantly suppressed the formation of colonies derived from AML CD34+ cells but not those from normal CD34+ cells. Moreover, fenretinide significantly reduced the in vivo engraftment of AML stem cells but not normal hematopoietic stem cells in a NOD/SCID mouse xenotransplantation model. Mechanistic studies revealed that fenretinide-induced cell death was linked to the rapid generation of reactive oxygen species, induction of genes associated with stress responses and apoptosis, and repression of genes involved in NF-κB and Wnt signaling. Further bioinformatic analysis revealed that the fenretinide-downregulated genes were significantly correlated with the existing poor-prognosis signatures in AML. Based on these findings, we propose that fenretinide is a potent agent that selectively targets LSCs, and may be of value in the treatment of AML.