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Chromosome translocations and covert leukemic clones are generated during normal fetal development
Hiroshi Mori1, Susan M Colman, Zhijian Xiao
1Leukaemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK.
Summary
Chromosomal translocations common in childhood leukemia are present in healthy newborns at a much higher rate than the disease risk. These prenatal events may require additional factors for overt leukemia development.
Area of Science:
- Hematology
- Genetics
- Pediatric Oncology
Background:
- Chromosomal translocations are characteristic of pediatric leukemia.
- These translocations often arise prenatally, suggesting they are initiating events.
- However, additional factors are needed for overt leukemia development, as indicated by low twin concordance rates.
Purpose of the Study:
- To determine if chromosome translocations and fusion genes, indicative of leukemia, are present in healthy newborns.
- To quantify the frequency of these genetic events in cord blood compared to leukemia risk.
Main Methods:
- Parallel reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time PCR (Taqman) screening for TEL-AML1 or AML1-ETO fusion genes.
- Single-cell analysis using cell enrichment and multicolor fluorescence in situ hybridization (FISH) staining.
Main Results:
- Common leukemia fusion genes (TEL-AML1, AML1-ETO) were found in cord blood at a frequency 100-fold higher than the leukemia risk.
- Translocations were confirmed in specific cell lineages (B lymphoid or myeloid) using multicolor FISH.
- Positive cells (10^-4 to 10^-3) indicated clonal expansion of progenitor cells.
Conclusions:
- Prenatal genetic events leading to leukemia fusion genes are common in newborns.
- These events occur in restricted cell populations and suggest early clonal expansion.
- Findings have significant implications for understanding leukemia pathogenesis, natural history, and etiology.