p53 tumour suppressor gene and RAS oncogenes: molecular analysis in the chronic and leukaemic phases of essential thrombocythaemia

Neri, Antonino; Fracchiolla, Nicola Stefano; Radaelli, Franca; Boletini, Alketa; Ribera, Sonia; Migliorini, Chiara; Trecca, Dino; Maiolo, Anna Teresa

doi:10.1046/j.1365-2141.1996.d01-1690.x

Cited by 13 publications

(9 citation statements)

References 9 publications

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“…In fact, we observed in the course of this study a type 1 case in which p53 mRNA expression was dramatically decreased in leukemia cells compared to that in c-Kit ϩ cells in control adult spleens (data not shown). Interestingly, it has been reported that mutation of the p53 gene is required for the acute crisis in essential thrombocytemia (21). Thus, these results suggest that the accumulation of GATA-1-knockdown progenitor cells, in combination with secondary genetic events, forms the molecular basis for the leukemic transformation in GATA-1.05/X mice.…”

Section: Discussionmentioning

confidence: 62%

Leukemogenesis Caused by Incapacitated GATA-1 Function

Shimizu

Kuroha²,

Onodera

et al. 2004

Molecular and Cellular Biology

102

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GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.

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Section: Discussionmentioning

confidence: 62%

Leukemogenesis Caused by Incapacitated GATA-1 Function

Shimizu

Kuroha²,

Onodera

et al. 2004

Molecular and Cellular Biology

102

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“…p53 mutations were detected in 37% of Ph 7 MPD in blast crisis and 2% of Ph 7 MPD in the chronic phase (Gaidano et al, , 1997Neri et al, 1996). p53 mutations in ALL is restricted to a small subset of cases.…”

Section: Ink4 Family Of Proteinsmentioning

confidence: 99%

Tumor suppressor genes in normal and malignant hematopoiesis

2002

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“…When data of both PV and ET blastic phase patients are combined, the frequency of TP53 mutations in these disorders approximates 50%. Notably, throughout the various stages of the clinical history of PV and ET, the occurrence of TP53 inactivation appears to cluster selectively with the blastic phase of the disease, since TP53 mutations in chronic phase patients are either absent (Gaidano et al, 1993, and this study) or extremely rare (Neri et al, 1996). Indeed, the analysis of consecutive samples obtained from the same patient at different stages of the disease, as performed in this study, indicates that tumor cells carrying TP53 genetic lesions accumulate at the time of transition from chronic to blastic phase disease.…”

Section: Discussionmentioning

confidence: 61%

Genetic lesions associated with blastic transformation of polycythemia vera and essential thrombocythemia

Gaïdano¹,

Pastore²,

Nomdedeu³

et al. 1997

Genes Chromosom. Cancer

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Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders that may progress to acute leukemia in a subset of patients. This study aimed at investigating the genetic lesions associated with the blastic transformation of PV and ET. A panel of PV and ET cases at different stages of disease was analyzed for the presence of genetic alterations of TP53, NRAS, KRAS, and MDM2 by a combination of mutational analysis and Southern blot hybridization. The occurrence of microsatellite instability (MSI) was also tasted in selected cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that alterations of TP53, NRAS, KRAS, and MDM2 do not contribute significantly to development of chronic phase PV and ET. Conversely, mutations of TP53 were detected in 7/15 (46.6%) blastic phase cases, including 3/5 PV and 4/10 ET. In blastic phase patients for whom the corresponding chronic phase DNA was also available, it could be documented that the genetic lesion had arisen at the time of blastic transformation. In addition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displayed MSI (one case of blastic phase PV). These data indicate that inactivation of TP53 is a relatively frequent event associated with the blastic transformation of PV and ET and may be responsible for the tumor progression of these disorders.

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p53 tumour suppressor gene and RAS oncogenes: molecular analysis in the chronic and leukaemic phases of essential thrombocythaemia

Cited by 13 publications

References 9 publications

Leukemogenesis Caused by Incapacitated GATA-1 Function

Leukemogenesis Caused by Incapacitated GATA-1 Function

Tumor suppressor genes in normal and malignant hematopoiesis

Genetic lesions associated with blastic transformation of polycythemia vera and essential thrombocythemia

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