RT Journal Article
SR Electronic
T1 New role of Epstein-Barr virus in pathogenesis of acute and chronic lymphocytic leukemia
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 197.11
OP 197.11
VO 202
IS 1 Supplement
A1 Laurynenka, Viktoryia
A1 Carter, Martha
A1 Parameswaran, Sreeja
A1 Chen, Xiaoting
A1 Kottyan, Leah C.
A1 Weirauch, Matthew T.
A1 Harley, John B
YR 2019
UL http://www.jimmunol.org/content/202/1_Supplement/197.11.abstract
AB Acute lymphoblastic leukemia (ALL) is the most common mortal cancer in children. Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia in western countries. B lymphocytes dominate the origin of both diseases. We have found a possible role for Epstein-Barr virus (EBV) in the origins of both ALL and CLL.We applied our strategy (Nat Genet 50:699, 2018) to determine whether the binding of EBV transcription factors (TFs) was concentrate at the 84 known risk loci for CLL and 16 loci for ALL. We evaluated 52 virally encoded TF ChIP-seq (chromatin immunoprecipitation with DNA sequencing) datasets and complemented this analysis with the results from 1535 human TF ChIP-seq datasets.We found that Epstein-Barr nuclear antigen leader protein (EBNALP), EBNA3C and EBNA2 were concentrated in the CLL loci by 3.7, 3.7 and 3.5-fold with p=4.89*10−19, p=2.74*10−11 and p=1.07*10−8, respectively. The viral (n=3) and human TFs (n=40) cluster together in an optimal subset of ~15 of the 84 known loci in CLL at p<10−6. Eighty percent of the most highly associated viral and human TF ChIP-seq datasets were collected from EBV transformed B cell lines in the Latency III program of viral expression, for which EBNALP, EBNA3C and EBNA2 are viral gene products.In ALL 3 of 16 loci were occupied by EBNA3ABC by a 17.7-fold enrichment with p=2.0*10−10. Among human TFs only c-MYC reached statistical significance binding 2 non-overlapping risk loci with 28.4-fold enrichment with p=2.9*10−10.These results nominate EBV for a role in the pathogenesis of CLL and ALL by a mechanism operating in transformed B cells through the EBV Latency III program of viral expression.