A type of childhood leukemia starts in the womb, yet can take 12 years to develop, scientists find

Scientists have discovered that a type of childhood leukemia starts with a genetic mutation in the womb and can take 12 years or more to progress into the life-threatening cancer - the longest “latency period” yet identified between the initiating genetic event and diagnosis of leukemia.

Discovery of such a long time lag between the initial event and full development of leukemia suggests that even some adult leukemia may start in the womb, the researchers conclude.

They report their findings in the current issue of the journal Blood (published May 15). The study was led by scientists at the University of California, San Francisco.

At least two separate genetic events are believed to cause most leukemia. By studying the similarities in the pregnancies which harbored the initial genetic mutation in this type of leukemia, scientists hope to identify the dietary, environmental or other causes for the potentially harmful mutation.

“Unraveling the causes and timing of the mutations that lead to leukemia, may allow us to predict and prevent this devastating disease,” said Joseph Wiemels, PhD, UCSF assistant professor of epidemiology and biostatistics, who led the research and is lead author on the paper.

Three years ago Wiemels and colleagues discovered that another, more common form of childhood leukemia also starts with a mutation in utero. But that leukemia is derived from a different form of blood cell and is confined mainly to ages two to five.

Leukemia arises in part from abnormal fusions of two genes which lead to abnormal proteins. Wiemels and his colleagues studied leukemias stemming from the fusion of genes known as AML1 and ETO.

This fusion is present in a type of childhood acute myeloid leukemia, the most difficult type of childhood leukemia to treat, Wiemels said.

The AML1 protein is a “master” regulator of gene activity for blood cell development from stem cells, Wiemels explained. If the AML1-ETO fusion occurs in just one out of the thousands of stem cells a person is born with, then the stage is set for a second unlikely gene mutation to trigger the leukemia, even if the second mutation occurs 12 years later, the research shows.

Acute myeloid leukemia accounts for about 15 percent of all childhood leukemia,
and the AML1-ETO fusion is found in about a fifth of these. About 200 children are diagnosed with this type of leukemia each year in the U.S. In addition, myeloid leukemia is the main form of leukemia in adults.

The scientists first sequenced the AML1-ETO gene fusion in patients at the time of leukemia diagnosis, using a novel technique known as long-distance inverse polymerase chain reaction. This allowed the researchers to scrutinize the unique nucleotide sequence of each patient’s gene fusion. They then used a sensitive DNA sequencing technique to trace the gene fusion back to the womb, using as a DNA sample previously stored “heel prick” blood spots customarily taken from children at birth.

The scientists now plan to determine whether other common leukemia gene fusions also occur in utero.  They will also examine, using epidemiological methods, whether environmental and dietary exposures or other factors, might have contributed to the formation of the gene fusions during pregnancy.

The research is funded by the National Institutes of Health and the Leukemia Research Fund UK.
Co-authors on the paper and collaborators in the research are Zhijian Xiao MD, postdoctoral fellow, Institute of Cancer Research, London; Patricia Buffler, Ph.D., professor of epidemiology; Xiaomei Ma, PhD, and Luoping Zhang, PhD, both research scientists; and Martyn Smith, PhD, professor of toxicology, all at UC Berkeley; Brian Dicks, BS, staff research associate; and John Wiencke, PhD, adjunct professor of epidemiology and biostatistics, both at UCSF; James Feusner, MD, head of hematology/oncology, Children’s Hospital Oakland; Ana T. Maia, BA, graduate research associate; Kathy Pritchard, professor, and Mel Greaves, professor of cell biology, all at the Institute of Cancer Research, London; and Helena Kempski, professor, Institute of Child Health, London.