HIGH-INCIDENCE OF POTENTIAL P53 INACTIVATION IN POOR OUTCOME CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA AT DIAGNOSIS

Previous studies have indicated that p53 gene mutations were an uncomm on event in acute lymphoblastic leukemia (ALL) in children. In one ser ies of 330 patients, p53 mutations were seen in fewer than 3%. We anal yzed bone marrow mononuclear cells derived from 10 children with ALL a t diagnosis who subsequently failed to achieve a complete remission or who developed relapse within 6 months of attaining complete remission for p53 gene mutations and mdm-2 overexpression. We found that three children had p53 gene mutations, and four overexpressed mdm-2. Also, e xperiments comparing relative levels of mdm-2 RNA and protein in these patients demonstrated that mdm-2 overexpression can occur at the tran scriptional and posttranscriptional level in primary leukemic cells. A lthough we were unable to link Waf-1 RNA expression with p53 status in childhood ALL, our data show potential p53 inactivation by multiple m echanisms in a large percentage of these patients and demonstrate that these alterations can be detected at diagnosis. Inactivation of the p 53 pathway may, therefore, be important in children with ALL who fail to respond to treatment and may be useful for the early identification of children requiring alternative therapies. (C) 1996 by The American Society of Hematology.