Chromosome translocations and covert leukemic clones are generated during normal fetal development

TLDR

Chromosomal translocations characteristic of pediatric leukemia often arise prenatally, as suggested by twin concordance studies and neonatal blood spot analyses, but additional postnatal exposures or genetic events are likely needed for overt disease. The study aims to test whether preleukemic chromosome translocations and fusion genes are detectable in healthy newborn blood at rates far exceeding leukemia risk. Using parallel RT‑PCR and real‑time PCR screening followed by single‑cell enrichment and FISH, the authors detected TEL‑AML1 or AML1‑ETO fusion genes in cord blood cells, confirming their presence in lineage‑restricted progenitors. The detected fusion genes were present in 10^−4 to 10^−3 of cord blood cells, indicating substantial clonal expansion of progenitors and underscoring important implications for childhood leukemia pathogenesis.

Abstract

Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins (≈5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase–PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO , are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10 −4 to 10 −3 ) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.