DNA DEMETHYLATION AND PERICENTROMERIC REARRANGEMENTS OF CHROMOSOME-1

Rearrangements in the vicinity of the centromere of chromosome 1 are o ver-represented in many types of human cancer and are a characteristic feature of a rare genetic disease called ICF (immunodeficiency, centr omeric heterochromatin instability, and facial anomalies). Evidence is presented that implicates DNA hypomethylation in the formation of the se pericentromeric chromosomal anomalies. The DNA methylation inhibito rs 5-azadeoxycytidine and 5-azacytidine, but not other tested genotoxi ns, induced the preferential formation of pericentromeric rearrangemen ts of chromosome 1 at a very high frequency in a pro-B-cell line (FLEB 14) and at a lower frequency in a mature B-cell line (AHH-1). These ab normal chromosomes appear identical to the diagnostic chromosomal aber rations in the ICE syndrome. A major component of the pericentromeric DNA in chromosome 1, satellite 2, was shown to be hypomethylated in an ICF B-cell line, although DNA from this cell line did not display det ectable overall hypomethylation. It is hypothesized that demethylation in certain DNA regions, including in pericentromeric satellite DNA, h elps lead to pericentromeric chromosomal rearrangements in lymphocytes from ICF patients and in normal lymphoblastoid cells incubated in vit ro with DNA demethylating agents. (C) 1997 Elsevier Science B.V.