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

Abstract

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.

Amplification or duplication of chromosome band 21q22 with multiple copies of the AML1 gene and mutation of the TP53 gene in therapy-related MDS and AML

“…In t-MDS and t-AML a similar amplification or duplication of chromosome band 11q23 including the unrearranged MLL gene has been observed in 17% of the patients closely associated with mutations of the TP53 gene. 16 As also AML1 amplification could be more common in t-MDS and t-AML than in de novo disease, we performed FISH for amplification or duplication of AML1 in 171 cases of t-MDS and t-AML, and examined positive cases for mutations of TP53.…”

Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia

“…They are never associated with cryptic genomic rearrangements of putative suppressor/oncogenes, which are known to be involved in therapy-related AML/MDS or with TP53 deletions such as are observed in secondary AML/ MDS with MLL and AML1 duplications/amplifications. 39,40 Consequently, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/or congenital genomic instability.…”

Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

“…34 In other cases, previously unidentified abnormalities have now been disclosed as duplications or amplifications of varying parts of the long arm of chromosome 11, including the 11q23 band and the unrearranged MLL gene, a phenomenon significantly associated with mutations of p53. 35 Experimental research indicates that the entire scenario of multiple chromosome aberrations and amplifications could result directly from p53 mutations. [36][37][38] As suggested for de novo AML, 39 deleted genes at 5q and acquired mutations of p53 possibly cooperate in leukemogenesis, also in t-MDS and t-AML.…”