Analysis of the p53 gene mutations in acute myelogenous leukemia: the p53 gene mutations associated with a deletion of chromosome 17

Kurosawa, M; Okabe, Mihiro; Kunieda, Y; Asaka, M

doi:10.1007/s002770050088

Cited by 3 publications

(4 citation statements)

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“…We verified the previously reported homozygous nonsense P53 mutation at codon 196 in Hut-78 (R196Stop) (Ri et al, 2009) and identified a homozygous missense mutation at codon 245 (G245S) of exon 7 in SeAx cells at the DNA-binding domain ( Table 1). The G245S is a nonfunctional mutation located in the mutational hot spot region (exons 5-9) of P53 and is observed in several cancers including hematological malignancies (Hu et al, 1992;Wada et al, 1993;Kurosawa et al, 1995;Villuendas et al, 1997;Wong et al, 1999;Leroy et al, 2002;Wojcik et al, 2005). Although the G245S mutation disrupts the DNA-binding surface, the overall scaffold is retained when the protein is folded (Wong et al, 1999), explaining the observed stabilization of p53 after nutlin-3a.…”

Section: Expression and Mutation Status Of P53 In Ctcl Cellsmentioning

confidence: 95%

MDM2 Inhibitor Nutlin-3a Induces Apoptosis and Senescence in Cutaneous T-Cell Lymphoma: Role of p53

Manfè

Biskup

Johansen

et al. 2012

Journal of Investigative Dermatology

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P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.

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Section: Expression and Mutation Status Of P53 In Ctcl Cellsmentioning

confidence: 95%

MDM2 Inhibitor Nutlin-3a Induces Apoptosis and Senescence in Cutaneous T-Cell Lymphoma: Role of p53

Manfè

Biskup

Johansen

et al. 2012

Journal of Investigative Dermatology

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“…7,13,15,19,32,33 Conversely, p53 mutations without cytogenetical alteration are a rare event. 32,33 In contrast, 10-30% of patients have a cytogenetical p53 deletion with wild-type configuration of the remaining allele.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,[13][14][15][16] However, in some cases the p53 deletion is present as a single chromosomal aberration and as a consequence treated in the standard risk group. So far, association of p53 mutations with poor overall survival (OS) has been described in AML, [17][18][19][20][21] but the prognostic impact of 17p aberrations in AML has been evaluated only in the context of complex aberrant karyotypes or other unfavorable cytogenetic markers. 5,6,16 Recently published data of 336 patients with AML including 9 patients with loss of 17p as sole abnormality revealed in vitro drug resistance and short OS in patients with 17p aberrations leading to p53 deletion.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Loss of p53Fa tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1)Fwas detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (Po0.001), À5 (Po0.001) and À7 (Po0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (Po0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (Po0.001), relapse risk (P ¼ 0.028) and overall survival (Po0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.

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“…It is less clear how tumor-suppressor genes complement other mutations in AML, but classical tumor-suppressor genes identified in AML include TP53 mutations in monosomy 17 AML (Fenaux et al, 1991;Kurosawa et al, 1995;Christiansen et al, 2001), RUNX1/ AML1 mutations in AML with chromosome 21 loss of heterozygosity (LOH) (Silva et al, 2003), and loss of the normal NF1 allele in children with neurofibromatosis type 1 and myeloid disorders including AML (Shannon et al, 1994).…”

Section: Introductionmentioning

confidence: 98%

Delineation of the minimal commonly deleted segment and identification of candidate tumor‐suppressor genes in del(9q) acute myeloid leukemia

Sweetser

Peniket

Haaland

et al. 2005

Genes Chromosomes & Cancer

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Deletion of the long arm of chromosome 9, del(9q), is a recurring chromosomal aberration in acute myeloid leukemia (AML) that is frequently associated with t(8;21). The critical gene products affected by del(9q) are unknown but likely cooperate with the AML1/ETO fusion gene created by t(8;21) in leukemogenesis. In 43 AML samples with del(9q), we used high-density microsatellite markers to define the commonly deleted region (CDR) to less than 2.4 Mb. We found no homozygous loss at any locus tested. The CDR contains 7 known genes, FRMD3, UBQLN1, GKAP42, KIF27, HNRPK, SLC28A3, and NTRK2, and 4 novel genes, RASEF, C9orf103, C9orf64, and C9orf76. In addition, TLE1 and TLE4 are adjacent to the CDR. We performed a comprehensive mutational analysis of the coding regions of all these genes. No sequence variations absent in normal controls were seen in more than a single del(9q) AML sample. Expression of 7 of the 10 genes examined was significantly down-regulated in del(19q)AML as compared with the CD34-purified progenitors from normal individuals, a pattern distinct from that seen in AML samples with a normal karyotype. The results of our studies are consistent with a model of tumor suppression mediated by haploinsufficiency of critical genes in del(9q) AML.

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Analysis of the p53 gene mutations in acute myelogenous leukemia: the p53 gene mutations associated with a deletion of chromosome 17

Cited by 3 publications

References 0 publications

MDM2 Inhibitor Nutlin-3a Induces Apoptosis and Senescence in Cutaneous T-Cell Lymphoma: Role of p53

MDM2 Inhibitor Nutlin-3a Induces Apoptosis and Senescence in Cutaneous T-Cell Lymphoma: Role of p53

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

Delineation of the minimal commonly deleted segment and identification of candidate tumor‐suppressor genes in del(9q) acute myeloid leukemia

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