Is CMV in utero the first event in pediatric ALL?

As reported in this issue of Blood, Francis et al hypothesized that a cytomegalovirus (CMV) infection in utero or a perinatal infection can initiate immune dysregulation during the critical development of fetal immune development and thereby play a role in childhood acute lymphoblastic leukemia (ALL).¹ 

The DNA virome of 268 children who later developed ALL was characterized from neonatal blood spots using unbiased next-generation sequencing (NGS) and compared with the virome of 270 non-ALL controls. The authors found a higher prevalence of CMV infection in the group with ALL; it was also more prominent in the Hispanic group of ALL. Several human tumor DNA viruses are known to be involved in the development of a malignant clone. Viruses can persist in the lymphoid cells and suppress double-stranded DNA-break repair, also known as DNA damage response.^2,3  Because the DNA damage response protects the genome from accumulating deleterious mutations, downregulation is associated with an increased risk of clonal development. A viral infection may generate the aberrant clones of lymphocytes that precede ALL development.^4,5 

Even though epidemiological evidence proposes that ALL may be initiated by an in utero infection with a common pathogen, the identification of such a pathogen has not been made.^6-9  Unlike viral-specific methods, unbiased NGS can provide a holistic picture of the virome of ALL patients, thus facilitating identification of viral candidates that might lead to ALL development. The role of unbiased NGS in the study of the human virome has been notable during the past decade, aiding in the detection of known and unknown viruses from both isolated cases and from major disease outbreaks.

However, in a recent study published in the British Journal of Cancer, NGS was used to characterize the DNA virome present in neonatal blood spots, which were analyzed with the aim of searching for potential infectious agents in children who later developed ALL. No clear association between infections with DNA viruses in utero and development of ALL was found.¹⁰ 

In this study, ALL as a diagnostic group was analyzed. The authors state that they did not analyze ALL subgroups. It is generally agreed that subgroups of ALL have different biological characteristics. This, of course, has to be taken into consideration when interpreting the results.

Analysis of acute myeloid leukemia was complicated by the low incidence in the study sample and the later onset of disease, with few positive cases, despite patients being older at the time of diagnosis, meaning they would have acquired a CMV infection earlier.

Several other questions are raised by this study: if there was a higher prevalence of CMV infections, were there also more birth defects? Why would the Hispanic group be more vulnerable to CMV infections and development of ALL?

In summary, this paper reported interesting results that need to be explored further in a larger study, including information concerning birth defects, subgroup analysis of ALL, epidemiological data, and examination of the Hispanic group. Likewise, data from earlier studies where CMV infection was not found need to be reexamined.