Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents.
Gene amplification is a rare phenomenon in acute leukemia, but recently amplification of specific chromosome bands containing genes rearranged in leukemia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 with 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of MLL were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together on the same chromosome arm representing amplification, 7 patients had single, extra duplicated copies of MLL, whereas both amplification and duplication were observed in the same cell in 1 patient. Comparative genomic hybridization demonstrated gain of varying, often large parts of 11q in five patients. The MLL gene was shown to be unrearranged in all 12 patients. Seven out of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients. Duplication or amplification of MLL was significantly associated with a complex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existence of a specific genetic pathway in t-MDS and t-AML with many previously unidentified chromosome aberrations demonstrated to represent extra copies of parts of 11q, including the unrearranged MLL gene.
Cytogenetic Laboratory, Department of Clinical Genetics, Section of Hematology/Oncology, The Juliane Marie Center, University Hospital, Copenhagen, Denmark. mka@rh.dk
M K
MK
Andersen
D H
DH
Christiansen
M
M
Kirchhoff
J
J
Pedersen-Bjergaard
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000477:Alkylating Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002869:Chromosome Aberrations / Q000139:chemically induced / Q000235:genetics*; D002871:Chromosome Banding; D025063:Chromosome Disorders; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D020732:Cytogenetic Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D020440:Gene Duplication; D016158:Genes, p53 / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D009693:Nucleic Acid Hybridization / Q000379:methods; D011519:Proto-Oncogenes; D012008:Recurrence; D014157:Transcription Factors
D000477:Alkylating Agents; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase