MECHANISMS OF P53 ALTERATION IN ACUTE LEUKEMIAS

Disruption of normal p53 expression is the most frequent genetic chang e occurring in various human solid tumors; it is mostly due to sequenc e alterations of the p53 coding region by missense mutations or to los s of an entire, functional allele of this gene. In the present study, possible mechanisms resulting in a disruption of regulated expression of wild-type p53 were examined in acute leukemias of either lymphoid ( ALL) or myeloid (AML) phenotype. p53 transcript accumulation, nucleoti de sequence and gene structure were analyzed in primary leukemic cells from 50 patients. p53-specific transcripts were detected in 26/26 cas es of ALL and 16/23 cases of AML using reverse transcriptase (RT)-PCR. Sequencing of transcripts did not reveal any point mutations or delet ions. Heterozygosity at a polymorphic Bg/II site within intron 1 was f ound in 4/28 leukemic samples, and loss of one allele was noted in one of these. In addition, a novel, leukemia-associated structural abnorm ality located within the 5' flanking region of the p53 gene and associ ated with the loss of heterozygosity was observed in cells from this p atient with ALL. The MDM2 gene which inactivates p53 by binding to it was neither amplified nor rearranged in 28 leukemias studied. Thus, di sruption of regulated p53 expression resulting in lack of detectable p 53 mRNA even by RT-PCR occurs in about 30% of cases of AML; however, p 53 alterations typical for human solid tumors are an infrequent event in most types of human acute leukemias.