GENETIC LESIONS ASSOCIATED WITH BLASTIC TRANSFORMATION OF POLYCYTHEMIA-VERA AND ESSENTIAL THROMBOCYTHEMIA

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 lesi ons associated with the blastic transformation of PV and ET. A panel o f 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 com bination of mutational analysis and Southern blot hybridization. The o ccurrence of microsatellite instability (MSI) was also tested in selec ted cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that al terations of TP53, NRAS, KRAS, and MDM2 do nor contribute significantl y 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 c hronic phase DNA was also available, it could be documented that the g eneric lesion had arisen at the time of blastic transformation, In add ition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displaye d MSI (one case of blastic phase PV). These data indicate that inactiv ation of TP53 is a relatively frequent event associated with the blast ic transformation of PV and ET and may be responsible for the tumor pr ogression of these disorders. (C) 1997 Wiley-Liss, Inc.