mutationof homozygotes for the 845G>A (C282Y) hereditary hemochromatosis promoter polymorphisms and liver abnormalities a Tumor necrosis factor

(BM) aspirates of 18 adults (22 to 76 years old) without neoplasia, 4 adults (25 to 76 years old) with hematopoietic neoplasia (non-Hodgkin lymphoma [NHL], myelodysplasia syndrome [MDS]), and 156 cord blood (CB) samples from healthy newborns. The samples were investigated by 3 independent laboratories in Goettingen, Vienna, and Hannover. Of 22 adult bone marrow samples, 6 (27%) were AML1/ETOpositive (Figure 1), of which 2 derived from patients with NHL. Of all samples, 2 exhibited neoplastic cells (NHL, MDS), of which one was AML1/ETO-positive. Of 156 CB samples, 63 (40%) were AML1/ETO-positive. We subjected 6 positive CB samples to real-time polymerase chain reaction (PCR) to determine the AML1/ETO copy number. Typical normalized ratios (AML1/ETO/housekeeping gene copies) of patients in CCR are 5 10 5 to 1 10 3, whereas patients with newly diagnosed AML range between 0.1 and 2.14.7 The ratios of the 6 CB samples ranged between 1.9 10 5 and 7.8 10 3, of which 3 out of 6 were comparable to patients with CCR. Assuming similar transcriptional levels, the number of AML1/ETO-positive cells in half of all positive healthy newborns may resemble that of patients with AML in CCR. We postulate that positive cells are either generated by permanent mutagenesis or are derived from aberrant hematopoietic stem cells. Since the gene fusion AML1/ETO is prone to be induced by radiation in vitro,9 an ongoing generation in all age groups by external mutagens may explain our observations. In this model it seems unlikely that AML1/ETO-positive cells have a survival advantage; otherwise, a much higher incidence in the elderly should be expected, though our observations may be influenced by the better cDNA quality of the cord blood samples. On the other hand, the t(8;21) may be generated in early hematopoiesis. Positive cells will then permanently derive from a positive stem cell pool but only few positive individuals may attract secondary genetic alterations and progress to AML. The latter mechanism is supported by the recent report of Wiemels et al on the detection of AML1/ETO in neonatal blood spots of children who developed a corresponding AML with more than 10 years latency.10