4-hydroxyestradiol and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Epidemiological data indicates increased risk of infant acute leukemia involving MLL gene aberrations with use of oral contraceptives. To determine whether estrogens might be implicated, we examined the effect of estradiol (E2) or 4-OH-E2 in an in vitro model of translocation susceptibility. Genomic DNA from the TK6 human lymphoblastoid cell line was screened by ligation mediated PCR and inverse PCR at a rearrangement hot spot within the MLL breakpoint cluster region to detect DNA aberrations. An increase in DNA double strand breaks was observed within this region after exposure to either E2 or 4-OH-E2. An increase in the frequency of MLL translocations was only found after exposure to E2. Induction of cleavage due to increased activation of apoptotic nucleases was excluded by pre-treatment with the pan-caspase inhibitor, zVAD.fmk. We conclude that concentrations of E2 and 4-OH-E2 that may occur during pregnancy, or during use of oral contraceptives, can cause aberrations of the MLL gene and could thus be a factor in the early events of leukemogenesis occurring in utero.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Aryl Hydrocarbon Hydroxylases; Cell Cycle; Cell Line, Tumor; Child; Chromosome Aberrations; Cloning, Molecular; Cytochrome P-450 CYP1B1; DNA Topoisomerases, Type I; Estradiol; Estrogens; Estrogens, Catechol; Female; Flow Cytometry; Histone-Lysine N-Methyltransferase; Humans; Infant; Myeloid-Lymphoid Leukemia Protein; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Receptors, Estrogen