Oncogene amplification in transforming myelodysplasia.
The MLL gene, located within band 11q23, has been shown to be involved in translocations with a large variety of reciprocal sites in both lymphoid and myeloid leukemia and has also been shown to undergo submicroscopic self-fusion/partial duplication. We report 29 patients with cytogenetic evidence of 11q23 alteration, all of which demonstrate molecular cytogenetic evidence of amplification of the MLL gene by fluorescence in situ hybridization (FISH). In all MLL cases, the patients were clinically classified as having transforming myelodysplasia (RAEB/RAEBT) or AML. An additional patient with AML was found by 24-color and gene-specific FISH to have AML1 oncogene amplification. Four patients had been previously diagnosed with cancer and had received topoisomerase II targeted drug therapy which is known to be associated with fusion transcripts involving the MLL and AML1 genes. MLL amplification appeared in various forms: an atypical banded region that bridges from 11q23 into a dicentric chromosome, expanded regions emanating from band 11q23, chromosome 11 paint-positive rings with "spoke-like" MLL amplification, and expansion at sites other than chromosome 11 (including extra markers) in the absence of one of the 11 homologues. The fluorescence pattern in most cases suggests palindromic duplication with neighboring sequences in the long arm of chromosome 11. As opposed to MYCN amplification in hsrs (homogeneously staining regions) and double minutes in neuroblastoma, amplification of MLL in most cases occurred at the site of the gene. All of our patients rapidly developed refractory AML. The frequency and clinical correlations of MLL gene amplification in leukemia will need careful follow-up, since the frequently cryptic amplification described in these cases may not generally provoke confirmatory FISH studies. The reported MLL cases represented about 1% of the total abnormal MDS/AML cases over 8 years. A common cytogenetic profile of 5 q-, -17/17 p-, -18/18 q-, and a missing or abnormal chromosome 11, may help direct appropriate follow-up studies. The MLL and the AML1 oncogenes appear to be the only oncogenes amplified at the natural site of the gene. Both genes also show a high degree of diversity of pathogenic mechanisms of leukemia evolution, including numerous reciprocal fusion genes in transformation to either AML or ALL and gain of function amplification.
Papenhausen
Peter R
PR
Laboratory Corporation of America, 1912 Alexander Drive, RTP, NC 27709, USA. papenhp@labcorp.com
Griffin
Sharon
S
Tepperberg
James
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein; D009436:Neural Tube Defects / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase