Prognostic significance of loss of a chromosome 17p and p53 gene mutations in blast crisis of chronic myelogenous leukaemia

Nakai, Hiroyuki; Misawa, Shinichi; Horiike, Shigeo; Takashima, T; Seriu, Taku; Nakagawa, Hitoshi; Fujii, Hiroshi; Shimazaki, Chihiro; Maruo, N; Akaogi, Teruaki; Uike, Naokuni; Abe, Tatsuo; Kashima, Kei

doi:10.1111/j.1365-2141.1994.tb04938.x

Cited by 20 publications

(4 citation statements)

References 9 publications

(3 reference statements)

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“…The BC stage of CML is commonly associated with nonrandom secondary chromosomal changes that, in addition to the t(9;22), include +Ph, +8, i(17q), +19, t(3;21)(q26;q22), and t(7;11)(p15;p15) (Prigogina et al,1978; Alimena et al,1987; Blick et al,1987; Melo et al,2003), or with mutations in the TP53, CDKN2A, RB1 , or RAS genes (Ahuja et al,1989; Kelman et al,1989; LeMaistre et al,1989; Feinstein et al,1991; Nakai et al,1992,1994; Mitani et al,1994; Nakai and Misawa,1995; Sill et al,1995; Nakamura et al,1996; Fioretos et al,1999; Beck et al,2000). However, the molecular mechanisms responsible for disease progression in CML have not been fully understood.…”

Section: Introductionmentioning

confidence: 99%

Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high‐resolution array‐based comparative genomic hybridization

Hosoya

Sanada

Nannya

et al. 2006

Genes Chromosomes & Cancer

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Chronic myelogenous leukemia (CML) evolves from an indolent chronic phase (CP) characterized by the Philadelphia chromosome. Without effective therapy, it progresses to an accelerated phase (AP) and eventually to a fatal blast crisis (BC). To identify the genes involved in stage progression in CML, we performed a genomewide screening of DNA copy number changes in a total of 55 CML patients in different stages with the use of the high-resolution array-based comparative genomic hybridization (array CGH) technique. We constructed Human 1M arrays that contained 3,151 bacterial artificial chromosome (BAC) DNAs, allowing for an average resolution of 1.0 Mb across the entire genome. In addition to common chromosomal abnormalities, array CGH analysis unveiled a number of novel copy number changes. These alterations included losses in 2q26.2-q37.3, 5q23.1-q23.3, 5q31.2-q32, 7p21.3-p11.2, 7q31.1-q31.33, 8pter-p12(p11.2), 9p, and 22q13.1-q13.31 and gains in 3q26.2-q29, 6p22.3, 7p15.2-p14.3, 8p12, 8p21.3, 8p23.2, 8q24.13-q24.21, 9q, 19p13.2-p12, and 22q13.1-q13.32 and occurred at a higher frequency in AP and BC. Minimal copy number changes affecting even a single BAC locus were also identified. Our data suggests that at least a proportion of CML patients carry still-unknown cryptic genomic alterations that could affect a gene or genes of importance in the disease progression of CML. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

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Section: Introductionmentioning

confidence: 99%

Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high‐resolution array‐based comparative genomic hybridization

Hosoya

Sanada

Nannya

et al. 2006

Genes Chromosomes & Cancer

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“…BCR–ABL protein is known to confer apoptotic resistance to DNA damage (Bedi et al , 1995; Nishii et al , 1996; Amarante‐Mendez et al , 1998) and has also been shown to prolong cell cycle arrest at the G2M checkpoint via increased tyrosine phosphorylation of CDK1, which can be abrogated by caffeine treatment (Nishii et al , 1996). p53 loss of function is a common abnormality in the transition from chronic‐phase CML to blast crisis, and is associated with drug resistance, suppression of apoptosis and poor prognosis (Nakai et al , 1994; Stuppia et al , 1997).…”

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confidence: 99%

p53‐mediated downregulation of Chk1 abrogates the DNA damage‐induced G2M checkpoint in K562 cells, resulting in increased apoptosis

Cummings¹,

Siitonen²,

Higginbottom³

et al. 2002

Br J Haematol

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Summary. BCR±ABL confers apoptotic resistance to a range of genotoxic agents, and this protection is mediated in part by prolonging the G2 checkpoint. The p53 tumour suppressor protein regulates the transcription of regulatory genes involved in cell cycle arrest and apoptosis. To investigate the effect of p53 on the BCR±ABL-mediated G2M checkpoint response, we transiently transfected the BCR± ABL-positive, p53-negative cell line K562 with wild-type human p53. The p53-transfected cells showed a decreased ability to arrest in G2 and an increase in apoptosis in response to etoposide treatment, relative to the control mock-transfected cells. p53-transfected and control cells were treated with etoposide and trapped at mitosis with nocodazole. The mitotic index of p53-transfected cells was higher than that of the control cells, which suggests that p53 abrogates the G2 checkpoint response to etoposide treatment in K562 cells. We found that the expression of the cell cycle checkpoint protein Chk1 was reduced in the etoposide-treated p53-transfected cells by 24 h, and this correlated with a reduction in the extent of etoposide-induced phosphorylation of CDK1 at tyrosine 15 (Y15). We conclude, therefore, that p53 overrides the strong G2 checkpoint response to etoposide in K562 cells, by directly or indirectly downregulating Chk1 expression, which, in turn, contributes to the proapoptotic effect of p53.

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“…8 Inactivation of p53 plays an important role in neoplastic transformation in solid tumors and it has also been reported in hematological malignancies in association with progression of disease. [9][10][11][12] Most often loss of 17p is accompanied by a complex aberrant karyotype, which in principle results in a poor outcome. 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.…”

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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Prognostic significance of loss of a chromosome 17p and p53 gene mutations in blast crisis of chronic myelogenous leukaemia

Cited by 20 publications

References 9 publications

Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high‐resolution array‐based comparative genomic hybridization

Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high‐resolution array‐based comparative genomic hybridization

p53‐mediated downregulation of Chk1 abrogates the DNA damage‐induced G2M checkpoint in K562 cells, resulting in increased apoptosis

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

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