P53 gene mutations in acute myeloid leukemia with 17p monosomy

Abstract

We looked for mutations of exons 5 to 8 of the P53 gene in 10 patients with acute myeloid leukemia (AML) and 17p monosomy, and 36 patients with AML and no cytogenetic abnormalities of 17p. DNA was analyzed by polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Four of the 10 patients with 17p monosomy showed point mutation, single-nucleotide deletion, or insertion in exons 7 or 8. By contrast, only 1 of the 36 patients with AML and no cytogenetic abnormalities of 17p showed a mutation of the P53 gene in exons 5 to 8 (P less than .01). These results suggest that alterations of the P53 gene may have a role in leukemogenesis in some cases of AML. The fact that P53 gene mutations occurred more often in patients with 17p monosomy seems to support the “recessive” model of tumor suppressive activity of the P53 gene rather than the “dominant” model, in which alteration of only one allele is sufficient for the development of malignancy.

Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia

“…Haferlach et al (27) reported that TP53 mutations were strongly associated with the complex karyotype in AML, but the association with dysplastic morphology was not evaluated; however, our results indicate that this genotype is closely associated with dysplastic morphology regardless of the history of MDS. It has been reported that TP53 mutation is associated with loss of chromosome band 17p13, where the TP53 gene is located (9,28). Deletion of 17p, which occurred by unbalanced translocation between chromosome 17p and another chromosome, monosomy 17 or i (17), is reportedly observed in 3-4% of AML and MDS and 10-15% of therapy-related MDS or AML (29)(30)(31)(32)(33).…”

“…Seven of the 11 TP53 mutated cases showed overlap mutations: two was overlapped with MLL-PTD and each one with NPM1, C ⁄ EBPA, AML1, cKIT, and FLT3 ⁄ ITD mutations. Cytogenetic analysis revealed that 10 TP53 mutated cases had abnormal karyotypes: eight were complex karyotype, five of which had a deleted chromosome 17, and each one was 46XY, del(5q) and 46XY, t(8;21), del (9). Importantly, one case with TP53 mutation and the karyotype 46XY, del(5q) harbored FLT3 ⁄ ITD, and one case with TP53 mutation and the karyotype 46XY, t(8;21), del(9) harbored cKIT mutation.…”

“…It has been generally considered that FLT3, cKIT, and N-RAS mutations are class I mutations, and C ⁄ EBPA and AML1 mutations, and AML1 ⁄ ETO, CBFB ⁄ MYH11, PML ⁄ RARA, and MLL abnormalities are class II mutations, while overlap mutations of these mutations between class I and class II or within the same class in a clinical sample are not fully characterized, and the positions of NPM1 mutation and the partial tandem duplication of the MLL gene (MLL-PTD) remain unclear. TP53 mutations are reportedly infrequent but are associated with a poor prognosis in de novo AML (9)(10)(11). In addition, an association between TP53 mutations and complex karyotype in therapy-related MDS and AML has been reported (12,13).…”

PRIMA‐1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

“…In AML, 17p mutation occurs in about 3-8% of cases and contributes to disease progression and development of resistance to drug therapy. p53 mutation is associated with advanced disease and short survival (Aas et al, 1996;Lai et al, 1995;Fenaux et al, 1991;Wattel et al, 1994).…”

“…In haematological malignancies, p53 mutations are less frequent than in solid tumours but are an important factor for response to chemotherapy and prognosis (Harris & Hollstein, 1993). In AML, p53 mutations occur in 5-8% (Fenaux et al, 1991;Stirewalt et al, 2001;Hu et al, 1992;Trecca et al, 1994). Aberration in the p53 gene is most frequently found in patients with secondary AML and complex karyotype.…”