A molecule expressed by the Epstein-Barr virus is found in the B cells, bone marrow and plasma of patients with chronic lymphocytic leukemia and is associated with reduced survival of those with the disease, researchers at MD Anderson Cancer Center have found.
Reporting in the June edition of EBioMedicine, a new joint publication of the Lancet and Cell Press, the researchers have demonstrated the presence and potential impact of the non-coding micro RNA called BHRF1-1, which is uniquely expressed by the virus.
Epstein-Barr virus, most famous as the cause of mononucleosis, has been known to play a role in B cell transformation to lymphoma, but its involvement in CLL, the most common adult leukemia, hasn’t been defined.
“Our findings suggest Epstein-Barr virus might play a role in CLL progression,” said corresponding author George Calin, M.D., Ph.D., professor of Experimental Therapeutics.
“Potential implications are the possibility of screening for people who are at risk for CLL due to family history of the disease and the use of the miRNA as a prognostic indicator,” Calin said. And BHRF1-1 could become a target both for vaccines to prevent CLL and for treatment with anti-miRNA compounds.
While the investigators identified the presence of the viral miRNA and associated it with shorter survival, Calin noted that they have not shown that it causes CLL. They did find that in some patients BHRF1-1 reduced expression of the tumor-suppressing gene TP53 and are further investigating that effect.
Micro RNAs (miRNAs) are short RNAs that do not code for translation into proteins. MiRNAs regulate a variety of processes by targeting messenger RNAs expressed by genes, destroying them or otherwise repressing their translation into proteins.
The team led by Calin and lead author Alessandra Ferrajoli, M.D., professor of Leukemia, hypothesized that Epstein-Barr virus miRNAs contribute to CLL progression and showed — through three different methods — that BHRF1-1 is present in patients’ B cells, bone marrow and plasma. Levels of the miRNA were significantly higher in patients compared to healthy individuals.
They also found high levels of expression of plasma BHRF1-1 are associated with high levels of miR-155, a cellular microRNA the team had previously found to be overexpressed in CLL patients and related to poor response to treatment.
BHRF1-1 overexpression associated with shorter survival
The investigators analyzed overall survival in 93 CLL patients. More than 80% of those with low BHRF1-1 expression survived to 10 years while half of those with high expression survived to 10 years. A validation set of 54 patients showed similar results.
A literature search indicated that BHRF1-1 targets the TP53 tumor suppressor gene. When they infected CLL cells that had intact TP53 with BHRF1-1 and measured TP53 protein levels, they found reduced levels of the protein in 10 of 17 cases, with four increases and three remaining stable.
Suppression of TP53 provides a possible explanation for why high levels of BHRF1-1 expression correlate with reduced survival. CLL patients with deletions on chromosome 17 that eliminate TP53 have a poor prognosis.
EBioMedicine also published a commentary on the paper that calls the research “an important breakthrough in the rapidly emerging field of circulating miRnomics.”
This research was funded in part as a pilot project by the Chronic Lymphocytic Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, designed to speed the conversion of scientific discoveries into clinical advances that reduce cancer deaths.