Backtracking Leukemia to Birth: Identification of Clonotypic Gene Fusion Sequences in Neonatal Blood Spots

Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-12, Vol.94 (25), p.13950-13954
Main Authors: Gale, Karin B., Ford, Anthony M., Repp, Reinald, Borkhardt, Arndt, Keller, Claudia, Eden, Osborn B., Greaves, Mel F.
Format: Article
Language:English
Subjects:
Artificial Gene Fusion
Babies
Base Sequence
Biological Sciences
Blood
Blood cells
Cell lines
Child, Preschool
DNA Primers - genetics
DNA, Neoplasm - blood
DNA, Neoplasm - genetics
DNA-Binding Proteins - genetics
Fetal Blood
Gene fusion
Genetics
Genomics
Histone-Lysine N-Methyltransferase
Humans
Identical twins
Infant
Infant, Newborn
Leukemia
Medical research
Medical screening
Molecular Sequence Data
Myeloid-Lymphoid Leukemia Protein
Nuclear Proteins - genetics
Pediatrics
Placenta
Polymerase chain reaction
Polymerase Chain Reaction - methods
Precursor Cell Lymphoblastic Leukemia-Lymphoma - blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma - etiology
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Proto-Oncogenes
Retrospective Studies
Transcription Factors
Transcriptional Elongation Factors
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Summary:Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.25.13950