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

Abstract

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.

N‐ras and p53 gene mutations in Japanese patients with myeloproliferative disorders

“…MPD seems to be heterogeneous diseases regarding molecular mechanisms in development and leukemic transformation and roles of the N-ras and p53 genes mutations during the course of MPD could differ in each subtype. However, it is reasonable to speculate that abnormalities in these two genes contribute independently to the occurrence and progression of MPD, because no concomitant mutations have yet been reported [2,3], including our study. To clarify the molecular mechanisms in pathogenesis of MPD, we need to simultaneously analyze many more samples for mutations of all candidate genes.…”

“…Gaidana et al analyzed samples of PV and ET in chronic phase and blastic phase for mutations of the p53, N-ras, K-ras, and MDM2 genes [3]. Samples in chronic phase were consistently all devoid of genetic lesions, but those in blastic phase showed point mutations in the p53 gene at a ratio of 3/5 in PV and 4/10 in ET and in the N-ras gene at a ratio of 0/5 in PV and 1/10 in ET, respectively.…”

“…It is plausible that leukemic transformation in MPD could be a result from accumulation of heterogeneous mutations of oncogenes and tumor suppressor genes. A few papers reported that mutations in the ras family and p53 genes appeared during the course of disease progression in MPD [2][3][4]. However, studies with a large number of MPD patients are still not conducted in Japan to elucidate molecular mechanisms in development and blastic transformation of MPD.…”

Current trends in essential thrombocythaemia

“…These results imply that p53 mutations may occur sporadically in patients with ET and that Ras genes are probably not involved in the pathogenesis of ET. Gaidano et al (1997), in contrast, only found p53 mutations in 4/10 patients in blast crisis and not in any chronic phase samples, nor in samples preceding those from the blastic phase. It is therefore possible that p53 mutations may be a feature of leukaemic transformation in ET.…”