Amplification of the MLL gene on double minutes, a homogeneously staining region, and ring chromosomes in five patients with acute myeloid leukemia or myelodysplastic syndrome

Gene amplification is one of the mechanisms for activating proto-oncogenes resulting in an enhanced expression of the corresponding gene product. By f luorescence in situ hybridization (FISH), amplification of the proto-oncoge ne MLL has been described only in seven patients with acute myeloid leukemi a (AML). We report five new patients (four had de novo AML, one had a de no vo myelodysplastic syndrome) displaying different mechanisms of MLL amplifi cation, suspected by G-banding and confirmed by FISH analysis. In two patie nts, MLL was amplified on double-minute chromosomes (dmins). In both cases, an interstitial deletion in 11q23 including the MLL gene was associated wi th the occurrence of the dmins containing MLL. As a rarely described mechan ism, MLL amplification in the form of size-variable ring chromosomes was ob served in two patients. Remodeling of the ring chromosomes leads to multipl e copies of MLL and obviously provided a selective growth advantage. In one of the two cases with ring chromosomes, the centromeric alpha-satellite DN A of the ring chromosome was not detectable. Our fifth patient showed the u nique finding of MLL amplification within a uniformly (homogeneously!) stai ned region in interaction with amplified ribosomal DNA sequences. Also, one of the patients with ring chromosomes exhibited the amplification of ribos omal DNA on the ring chromosomes. The transcriptionally active genes for ri bosomal RNA could probably enhance the expression of MLL. In one of our fiv e patients, we found the new combination of concomitant amplification of th e proto-oncogenes MLL and MYC. (C) 2000 Wiley-Liss, Inc.