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

Abstract

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.

Genetics of therapy-related myelodysplasia and acute myeloid leukemia

“…29,36 This mutation was highly significantly related to the cytogenetic defects 5qÀ/À5 (Table 2), as 26/34 patients with p53 mutations presented 5qÀ/À5, to previous therapy with alkylating agents 29 and to complex karyotypes with highly rearranged chromosomes. 37 Duplication or amplification of chromosome bands 11q23 and 21q22, including the unrearranged MLL and AML1 genes, were occasionally observed in t-MDS or t-AML 38,39 and closely associated with mutations of p53 ( Figure 2). …”

“…Particularly in t-MDS and t-AML, a decreased dose of the p15 INK4B -63 , the EGR1- 41 or the CTNNA1-42 encoded proteins as a result of promoter methylation or haploinsufficiency must be considered. Also, an increased dose of the unrearranged MLL and AML1 gene products caused by chromosome duplication or amplification 38,39,[64][65][66] may represent examples of gene dose effects in AML.…”

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…11 The close association between 5qÀ/À5 and mutation of p53 is confirmed by our so far unpublished follow-up study showing that in total 25 of the 34 patients in pathway II (77%) presented a p53 mutation (Po0.0001). Deletion or loss of 17p resulting in loss of heterozygosity of p53, 11 complex karyotypes, 11 chromosome derivatives composed of material from at least three different chromosomes 19 and amplification or duplication of chromosome bands 11q23 20 and 21q22 21 are all characteristic of pathway II (Figure 1). In pathway II mutation of the RAS or the FLT3 gene was observed in only a single patient each, and only three patients presented AML1 point mutations including two cases with an additional 7qÀ/À7.…”

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.…”