||5R01CA268494-02 Interpret this number
||University Of Southern California
||Cytomegalovirus as an Etiologic and Clinico-Pathogenic Factor in Childhood Acute Lymphoblastic Leukemia
Childhood acute lymphoblastic leukemia (ALL) is most common cancer in children (age 0- 14 years). Despite
improvements in treatment, survivors face a lifelong battle with negative health effects of treatment, making
prevention a priority. The lack of modifiable etiological factors has been a major barrier to prevention, but we
recently made a groundbreaking (albeit preliminary) discovery that neonatal cytomegalovirus (nCMV) infection
is a strong risk factor for childhood ALL (estimated odds ratio = 3.7) in a small study with 268 cases and 270
controls. In the same study, we also found CMV sequences within pre-treatment diagnostic tumor tissue. In
addition, we conducted a population-based study linking medical records and cancer registry data in Sweden,
which revealed a relative risk over 10 for early CMV infection and the child’s hematologic malignancy
diagnosis. We propose here to definitively assess the epidemiology of CMV and ALL including CMV’s impact
on the ALL tumor genome. We hypothesize that nCMV will contribute to ALL incidence and create specific
mutational signatures present in ALL tumor genomes known to be associated with viral and infectious
etiologies. In our first aim, we will better define the role of nCMV infection as an ALL risk factor in a study with
over 3800 cases and 4897 controls, accounting for other risk factors such as birthweight, birth order, mode of
delivery, polygenic risk score for ALL and parental ages neonatal immune phenotype, as well as the role of
maternal CMV infection status during pregnancy. We will also assess whether CMV contributes to the higher
risk of ALL in Latinos compared to other groups. As a second aim, we will test 1,020 children for CMV
involvement at birth and within their matched ALL tumor genomes collected at diagnosis. We will investigate
the presence of the APOBEC and Recombinase Activating Gene (RAG), virally-associated mutational
signatures, within tumors that were nCMV positive compared to those from children negative for the virus. This
research will leverage exceptional resources, including archived newborn blood specimens and population-
based childhood ALL cases and controls, and maternal blood specimens collected during mid-pregnancy. In
addition, the proposed study benefits from a high fraction of Latinos in the study population who carry a
disproportionate burden of childhood ALL, include advanced laboratory techniques to identify neonatal and
maternal CMV infection that have been refined in our laboratory, and will evaluate directly a mutation signature
putatively caused by the virus. CMV is a highly adept immune manipulator. Identification of CMV as an
etiologic agent in childhood ALL could create an unprecedented target for leukemia prevention, either by
vaccination against CMV infection or manipulation of the host response to CMV infection after birth. In either
scenario, this proposal will better characterize the role of CMV in the genesis of childhood ALL and have
profound impact from a prevention perspective. As CMV is also responsible for congenital hearing loss and a
host of other neurological outcomes, our research will impact childhood health apart from leukemia.
Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children.
, Arroyo K.
, Metayer C.
, Kang A.Y.
, de Smith A.J.
, Wiemels J.L.
International journal of cancer, 2023-03-01; 152(5), p. 845-853.
Does Cytomegalovirus Play a Role in Pediatric Lymphoblastic Leukemogenesis?
JAMA network open, 2023-01-03; 6(1), p. e2250226.