Joseph L Wiemels, PhD, is a professor at University of California-San Francisco’s department of epidemiology and biostatistics, and co-president of the Brain Tumor Epidemiology Consortium. His research focus is the molecular epidemiology of childhood cancers. Dr Wiemels pioneered the identification of prenatal and early childhood gene-mutation events’ roles in pediatric leukemogenesis. He has published more than 80 scientific papers on the epidemiology of leukemia.

In this question-and-answer session, Cancer Therapy Advisor asked Dr Wiemels about emerging evidence that viral infection might play an important role in childhood leukemogenesis. He and others coauthored a recent gene-sequencing study, published in Blood, that identified cytomegalovirus (CMV) infection as a potential risk factor for pediatric acute lymphoblastic leukemia (ALL), but not acute myeloid leukemia (AML).1

The team found that CMV is prevalent in pretreatment bone marrow among children with ALL, and that in-utero CMV infection is a risk factor for ALL, an association that was particularly strong among Hispanic children.

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Cancer Therapy Advisor (CTA): How did the team discover the CMV association with pediatric ALL?

Dr Wiemels: We used 2 types of biological samples obtained from children with leukemia at their diagnostic visit to the hospital; 1 sample was the leukemia cells themselves (purified from their bone marrow). In these cells we sequenced total RNA, which means all genes currently expressed in these cells. The point was to search for active pathogens. After accounting for all the normal cellular genes we compared the ‘unmapped’ sequences to databases of known viruses, and found a variety of viruses and bacteria sequences.

The only virus that showed up in all of the ALL subjects and not at all in AML was CMV.

The second sample we used was blood plasma from a set of children with leukemia (ALL compared to AML). In this case, we made an effort to remove all stray RNA and DNA by purification and digestion with enzymes, and isolated viral particles, which protect their nucleic acids.

We then opened these viral particles and sequenced, finding CMV in most of the ALL patients and only 1 of the AMLs. From these 2 assays (which were on different sets of patients) we found evidence that CMV is the only virus to distinguish ALL from AML.

This does not rule out CMV as a potential opportunistic infection in these immunosuppressed children, but it does present the possibility that CMV plays a role in ALL. Still, CMV is a ubiquitous virus but has an average seroconversion age of 28 years old, so it is unusually frequent in these ALL patients (at a minimum). 

After this result we wondered whether there may be a particular timing of infection by CMV that was critical for a role in ALL. So, we decided to check the Guthrie cards.