Researchers led by a scientist who joined the UC San Francisco faculty last week are reporting that a genetic mutation implicated in a common form of childhood leukemia appears to occur in the womb.
Their study, reported in the Oct. 30 issue of Lancet, indicates that two genes, known as TEL and AML1, aberrantly fuse during the development of the blood cells in the fetus. The fused genes then produce a protein that is potentially oncogenic.
Based on previous research, the team says the fused state of the two genes is not inherited; instead, it occurs during pregnancy, probably as a result of a developmental accident, as opposed to exposure to an environmental mutagen.
Importantly, the fusion of the TEL and AML1 genes is not sufficient to cause development of the disease, known as "common acute lymphoblastic leukemia," the researchers said. All people have two copies of every gene, and earlier work by the researchers on identical twins with leukemia indicates that a second genetic alteration - involving the second copy of the TEL gene, one of the two so-called "alleles" -- occurs post-natally to actually nudge blood cells into a leukemic state.
"It may be that the normal TEL allele successfully suppresses the function of the aberrant TEL-AML1 protein resulting from the fusion, so full-blown leukemia doesn't occur," said the lead author of the study, Joseph Wiemels, PhD, now a UCSF assistant research molecular epidemiologist. "One theory is that the second, normal TEL allele is lost, and that at this point the fused TEL-AML1 protein becomes oncogenic."
The researchers don't know what leads to the initial genetic abnormality in the womb, but their discovery, said Wiemels, will provide researchers with a time frame for analyzing the development of the mutation. Studies indicate that the second genetic alteration may result from an abnormal reaction to common childhood infections.
Wiemels conducted the research in the laboratory of Mel Greaves, PhD, professor of cell biology, in the Leukaemia Research Fund for Cell and Molecular Biology at the Institute of Cancer Research, in London. The work was conducted in collaboration with researchers at the University of Milan, Italy and the Royal Manchester Children's Hospital, UK.
Common acute lymphoblastic leukemia usually develops in children between the ages of two and five years, and accounts for approximately 80 percent of the cases of childhood leukemia. It is diagnosed in approximately 2,500 children in the United States each year, and is curable with chemotherapy in about three-quarters of patients.
The researchers conducted their study by using a highly sensitive probe to scrutinize minute numbers of leukemia cells in blood samples previously collected from newborns who during childhood were diagnosed with leukemia. These samples, known as Guthrie cards, or blood spots, are routinely drawn from newborns, with a prick to the heel, in order to diagnose such genetic disorders as thalassemia and Phenylketonuria, or PKU.
The scientists examined blood samples from one set of identical twins, and from nine other children, and detected the mutation in the twins and in six of the nine singletons. In the three other cases, the mutation was not revealed, perhaps, said Wiemels, because the pre-leukemic cells were too rare to be detected in the miniscule blood spot. The identical twins most strongly demonstrated that the mutation occurred prenatally because the samples from both newborns, who have the same genes, revealed the mutation.
"Our previous studies of identical twins indicate a prenatal origin of childhood leukemia that in some cases was diagnosed in children up to 14 years of age. That evidence, combined with the present study, suggests that childhood leukemia may regularly be initiated before birth," said Wiemels.
Co-authors of the study were Giovanni Cazzaniga, PhD, Maria Daniotti, BSc, Giuseppe Masera, MD, and Andrea Biondi, MD, of Centro Ricerca Tettamanti, Clinica Pediatrica, Universita di Milano, Ospedale San Gerardo, Milan, Italy; Osborn B. Eden, FRCP, of the Academic Unit of Paediatric Oncology, Christie Hospital NHS Trust, Manchester, UK; G. M. Addison, FRCPath, of the Department of Clinical Biochemistry, Royal Manchester Children's Hospital, Manchester; and V. Saha, FRCPCH, of the Department of Paediatric Haematology and Oncology, Royal London Hospital, London.
The study was supported by the Leukaemia Research Fund, the Cancer Research Campaign, and the Fondazione Tettamanti, Associazione Italiana per la Ricerca sul Cancro and MURST.
Journal
The Lancet