Genomic evidence for a prenatal origin of childhood acute myeloid leukemia

A team of researchers from the Institute of Oncology of the University of Oviedo (IUOPA), the Josep Carreras Leukemia Institute, the University of Barcelona and the Cancer Biomedical Research Center Network (CIBERONC) have demonstrated that some childhood leukemias do not develop until several months after birth, but arise during fetal development.

Acute myeloid leukemia is the second most common type of acute childhood leukemia and may be diagnosed within the first few months of life. Due to the early onset of the disease, it was suspected that the tumors may have developed before birth. However, a lack of prenatal or birth samples has made this theory difficult to prove.

The opportunity to study the origins of this leukemia arose from the case of a 5-month-old infant diagnosed with acute myeloid leukemia at the Niño Jesús Hospital in Madrid.”

Pablo Menéndez, ICREA Professor at the University of Barcelona and Josep Carreras Institute

“Parents who banked umbilical cord blood have opened up avenues of research that could not be addressed before,” the researchers added.

Using precision medicine techniques, the researchers analyzed the entire genome of the tumor. Whereas thousands of mutations are detected in adult tumors, only two chromosomal abnormalities were identified in this leukemia. “The genome analysis allowed us to design personalized diagnostics to monitor the disease,” says Xose S. Puente, professor of biochemistry at the University of Barcelona and professor of biochemistry and molecular biology at the University of Oviedo. “But these data raise new questions, such as when did the tumor develop and in what order did these mutations appear,” he emphasizes. These questions are difficult to answer, since such studies require taking blood samples from the baby before the diagnosis, which is not possible in most cases. But in this particular case, the presence of frozen umbilical cord samples allowed the researchers to isolate the different blood cell populations at birth and to find out whether any of the chromosomal abnormalities detected in the tumor were already present during fetal development.

The study revealed that a translocation between chromosomes 7 and 12 was already present in some of the hematopoietic stem cells from the umbilical cord. In contrast, another chromosomal abnormality, trisomy 19, was absent in the fetus but was found in all tumor cells, suggesting that it contributes to the increased malignancy of the leukemia cells. “These data are of great importance for understanding the progression of a devastating disease and the presence of this umbilical cord sample was essential to carry out studies that were not possible before in acute myeloid leukemia,” added Thalia Velasco, researcher at the Josep Carreras Institute and the University of Barcelona, ​​co-leader of the study.

In this study, we not only reproduced the genomic changes that cells undergo to give rise to leukemia, but also identified a molecular mechanism not previously observed in this type of leukemia. This mechanism leads to the activation of a gene called MNX1, which is frequently altered in this type of tumor. Knowledge of these alterations is essential for the development of cellular and animal models to understand disease progression and develop new therapies to treat these pathologies.

The study was carried out by Thalia Velasco and Pablo Menéndez, professors of biochemistry and molecular biology at the IUOPA University of Oviedo, with the cooperation of the Niño Jesus University Pediatric Hospital, the Central University Hospital of Asturias, the Institute of Biomedicine and Biotechnology of Cantabria, and the Health Institute of La Princesa de Madrid.

This research was made possible thanks to the collaboration of parents and funding from the Ministry of Science, Innovation and Universities, the European Research Council, the AECC Science Foundation, the Unoentrecienmil Foundation, the “La Caixa” Foundation, the Catalan Government, CIBERONC and the III Health Institute.