Researchers led by a scientist who joined the UC San Francisco faculty lastweek are reporting that a genetic mutation implicated in a common form ofchildhood 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 bloodcells in the fetus. The fused genes then produce a protein that is potentiallyoncogenic.
Based on previous research, the team says the fused state of the two genes isnot inherited; instead, it occurs during pregnancy, probably as a result of adevelopmental accident, as opposed to exposure to an environmental mutagen.
Importantly, the fusion of the TEL and AML1 genes is not sufficient to causedevelopment of the disease, known as "common acute lymphoblastic leukemia," theresearchers said. All people have two copies of every gene, and earlier work bythe researchers on identical twins with leukemia indicates that a secondgenetic alteration - involving the second copy of the TEL gene, one of the twoso-called "alleles" -- occurs post-natally to actually nudge blood cells into aleukemic state.
"It may be that the normal TEL allele successfully suppresses the function ofthe aberrant TEL-AML1 protein resulting from the fusion, so full-blown leukemiadoesn't occur," said the lead author of the study, Joseph Wiemels, PhD, now aUCSF assistant research molecular epidemiologist. "One theory is that thesecond, normal TEL allele is lost, and that at this point the fused TEL-AML1protein becomes oncogenic."
The researchers don't know what leads to the initial genetic abnormality in thewomb, but their discovery, said Wiemels, will provide researchers with a timeframe for analyzing the development of the mutation. Studies indicate that thesecond genetic alteration may result from an abnormal reaction to commonchildhood infections.
Wiemels conducted the research in the laboratory of Mel Greaves, PhD, professorof cell biology, in the Leukaemia Research Fund for Cell and Molecular Biologyat the Institute of Cancer Research, in London. The work was conducted incollaboration with researchers at the University of Milan, Italy and the RoyalManchester Children's Hospital, UK.
Common acute lymphoblastic leukemia usually develops in children between theages of two and five years, and accounts for approximately 80 percent of thecases of childhood leukemia. It is diagnosed in approximately 2,500 childrenin the United States each year, and is curable with chemotherapy in aboutthree-quarters of patients.
The researchers conducted their study by using a highly sensitive probe toscrutinize minute numbers of leukemia cells in blood samples previouslycollected from newborns who during childhood were diagnosed with leukemia.These samples, known as Guthrie cards, or blood spots, are routinely drawn fromnewborns, with a prick to the heel, in order to diagnose such genetic disordersas thalassemia and Phenylketonuria, or PKU.
The scientists examined blood samples from one set of identical twins, and fromnine other children, and detected the mutation in the twins and in six of thenine singletons. In the three other cases, the mutation was not revealed,perhaps, said Wiemels, because the pre-leukemic cells were too rare to bedetected in the miniscule blood spot. The identical twins most stronglydemonstrated that the mutation occurred prenatally because the samples fromboth newborns, who have the same genes, revealed the mutation.
"Our previous studies of identical twins indicate a prenatal origin ofchildhood leukemia that in some cases was diagnosed in children up to 14 yearsof age. That evidence, combined with the present study, suggests thatchildhood 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, ChristieHospital NHS Trust, Manchester, UK; G. M. Addison, FRCPath, of the Departmentof Clinical Biochemistry, Royal Manchester Children's Hospital, Manchester; andV. 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 ResearchCampaign, and the Fondazione Tettamanti, Associazione Italiana per la Ricercasul Cancro and MURST.
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