Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype

Abstract

We examined chromosomes and molecular aberrations in 21 patients with therapy-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All patients showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (−5/5q− and/or −7/7q−) were identified in 12 patients. Among these 12, six patients (50%) harbored a TP53 mutation, and two of five examined showed microsatellite instability, suggesting replication error (RER ؉ ) phenotype. Meanwhile, among the other nine patients without −5/5q− and/or −7/7q−, none harbored a TP53 mutation, and none of five examined showed RER ؉ phenotype. Thus, TP53 mutations and RER ؉ phenotype were preferentially associated with specific chromosomal losses in t-AML/MDS. We then screened for mutational events in representative DNA mismatch repair genes; exons 5-7 and 12-15 of the hMSH2 gene and exon 9 of hMLH1. Notably, two unrelated patients showing RER ؉ phenotype had an identical missense alteration at codon 419 of hMSH2 in their marrow cells and fibroblasts, which were not found in 120 DNA samples from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER ؉ phenotype accompanying an hMSH2 alteration to the development of therapy-related AML/MDS in association with TP53 mutations and specific chromosomal losses, and suggests that some patients may be predisposed to myelodysplasia after chemotherapy for their primary tumor.

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

“…Independent of the state of complexity, there were significant higher amounts of CD34 þ cells. Published in vitro investigations 27,28 indicated that the loss of p53 function could cause cell-cycle arrest in a very primitive stage of 14,21,29,30 Furthermore, we could see an inverse correlation between p53 deletion and the molecular risk factors FLT3-ITD and NPM1 mutation.…”

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

“…5 On the other hand, patients belonging to pathway II frequently present a complex karyotype and a mutation of p53, whereas pathway I has a very low frequency of p53 mutations. 22,34 However, we have focused on the pivotal role of AML1 mutations, rather than cytogenetic abnormalities, during the development of MDS/AML. We are trying to define the disease entity of 'MDS/AML with AML1 mutation', which could be considered for inclusion in the recurrent genetic abnormalities under the WHO classification.…”

Tumor suppressor genes in normal and malignant hematopoiesis

“…Studies of therapy-related AML/ MDS found p53 mutations in 30% of cases, with the majority of the mutated samples showing a loss of the wild type p53 allele (Horiike et al, 1999;Christiansen et al, 2001). In two studies involving 351 patient samples of AML and MDS (Fenaux et al, 1991;, 38 of 59 samples (64%) that showed a deletion of chromosome 17p had a point mutation of the remaining p53 allele.…”