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 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.
Gale
K B
KB
Leukaemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.
Ford
A M
AM
Repp
R
R
Borkhardt
A
A
Keller
C
C
Eden
O B
OB
Greaves
M F
MF
D019677:Artificial Gene Fusion; D001483:Base Sequence; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005312:Fetal Blood; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000209:etiology / Q000235:genetics*; D011519:Proto-Oncogenes; D012189:Retrospective Studies; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors
D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase