Acute lymphoblastic leukemia (ALL) originates in the bone marrow and involves the accumulation of malignant whote blood cells, which can interfere with the production of the healthy counterpart. This common blood cancer occurs mostly in adults, killing about 100,000 people worldwide each year. ALL is also the most common form of cancer among children, accounting for approximately 20% of malignancies seen in individuals under the age of 20. High penetrance genetic predispositions, such as Down syndrome, account for less than 5% of ALL cases. Environmental risk factors have also been hypothesized, such as exposure to solvents and ionizing radiation; however, the data are inconclusive. The causes of nearly all cases of ALL remain mostly unclear. CMV has also emerged as a possible risk factor for ALL in recent years. CMV (or herpesvirus HHV 5) can cause transplacental infection at the time of pregnancy. Studies indicate that prenatal CMV infection significantly increases the chances of suffering from pediatric ALL.
As CMV screening among newborns is under development, it is critical to determine by replication whether CMV infection at birth can lead to ALL. The increase in the incidence of ALL observed in high-income countries over the previous decades is attributed at least in part to changing patterns of early childhood encounters with infectious stimuli. Two nonexclusive hypotheses describe these patterns: (1) delayed exposure to common infections and microbial colonization in childhood can lead to aberrantly vigorous and harmful immune responses later in childhood, increasing the risk of ALL, and (2) one The specific virus that causes leukemia can infect children who are immunologically “naïve” to such a virus in situations where increased community mixing occurs. The CMV-LLA association does not fit conveniently into either of these scenarios; certainly neonatal infection cannot be described as delayed. As for the second hypothesis, CMV has never been proven to be a cancer virus.
Its ubiquitous prevalence in the population (>80% seropositive worldwide, both in high-income and developing countries) argues that CMV itself should not be the causative agent given the rarity of ALL in children . The incidence of congenital CMV infection did not change simultaneously over the time period that the incidence of ALL increased. In a newly published investigation, researchers determined the prevalence of CMV infection among ALL patients and matched controls. In a cohort of 1199 ALL-eligible patients and 4796 matched controls, ALL cases had higher mean birth weights than controls. There were 153 cases with mothers aged 35 and older compared with 547 controls. All patients had a considerably higher incidence of congenital anomalies than controls. CMV DNA was found in six of 1189 ALL patients and 21 of 4756 controls. All ALL patients and controls had chances of CMV infection that were not statistically different. Furthermore, there were no T-ALL patients who tested positive for CMV.
In an unparalleled study, patients with hyperdiploid ALL were 6 times more likely to be CMV positive than all controls. Exposure to CMV leads to lifelong infections and impaired immune function; exposure in the neonatal period (rather than later in childhood or adulthood) may lead to the development of immune function that promotes or enables oncogenic stimuli or, as explained in Geris et al., may affect bone marrow stem cell growth. Early exposure to CMV can therefore alter the hematopoietic state upon which other infectious stimuli play a more direct causal role. Neonatal CMV infection is therefore likely an adjuvant to Greaves’ hypothesis of delayed infection rather than representing an entirely new causal pathway for ALL. Therefore, CMV may not be a prevalent direct risk factor for ALL.
- edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Scientific references
Gallant RE et al. Int J Cancer. 2023; 152(5):845-853.
Wiemels JL. JAMA Netw Open. 2023; 6(1):e2250226.
Geris JM et al. JAMA Netw Open. 2023; 6(1):e2250219.
Nauclér CS et al. Oncotarget. 2019; 10(42):4333-4347.
Greaves M. Nature Rev Cancer. 2018; 18(8):471-484.
Francis SS et al. Blood. 2017; 129(12):1680-1684.
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