THE RELATIONSHIP BETWEEN THIOPURINE METHYLTRANSFERASE ACTIVITY AND GENOTYPE IN BLASTS FROM PATIENTS WITH ACUTE-LEUKEMIA

The level of expression of the enzyme thiopurine methyltransferase (TP MT) is an important determinant of the metabolism of thiopurines used in the treatment of acute lymphoblastic leukemia (ALL) and acute myelo id leukemia (AML), Studies in red blood cells (RBC) have shown that TP MT expression displays genetic polymorphism with 11% of individuals ha ving intermediate and one in 300 undetectable levels. The genetic basi s for this polymorphism has now been elucidated and polymerase chain r eaction (PCR)-based assays described for the most common mutations acc ounting for reduced activity. In previous studies, genotype has been c orrelated with red blood cell activity. In this report, we describe th e relationship between genotype and TPMT activity measured directly in the target of drug action, the leukemic cell. We have demonstrated th at the TPMT activity in lymphoblasts from 38 children and adults found by PCR to be homozygotes (1/*1) was significantly higher than that i n the five heterozygotes (1/*3) detected (median, 0.25 v 0.08, P < .0 02, Mann-Whitney U), Similar results were obtained when results from c hildren were analyzed separately, However, comparison of activity in b lasts from AML and ALL showed a higher level in the former (0.35 v 0.2 2 nU/mg, P < .002, n = 17, 35), suggesting that facto rs other than ge notype may also influence expression. (C) 1998 by The American Society of Hematology.