Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2856-2862
The Relationship Between Thiopurine Methyltransferase Activity
and Genotype in Blasts From Patients With Acute Leukemia
Sally A. Coulthard,
Christopher Howell,
Jill Robson, and
Andrew G. Hall
From the LRF Molecular Pharmacology Specialist Programme, Cancer
Research Unit, Medical School, University of Newcastle, Newcastle, UK.
The level of expression of the enzyme thiopurine methyltransferase
(TPMT) is an important determinant of the metabolism of thiopurines
used in the treatment of acute lymphoblastic leukemia (ALL) and acute
myeloid leukemia (AML). Studies in red blood cells (RBC) have shown
that TPMT expression displays genetic polymorphism with 11% of
individuals having intermediate and one in 300 undetectable levels. The
genetic basis for this polymorphism has now been elucidated and
polymerase chain reaction (PCR)-based assays described for the most
common mutations accounting for reduced activity. In previous studies,
genotype has been correlated with red blood cell activity.
In this report, we describe the relationship between genotype and TPMT
activity measured directly in the target of drug action, the leukemic
cell. We have demonstrated that the TPMT activity in lymphoblasts from
38 children and adults found by PCR to be homozygotes (*1/*1) was
significantly higher than that in the five heterozygotes (*1/*3)
detected (median, 0.25 v 0.08, P < .002, Mann-Whitney
U). Similar results were obtained when results from children were
analyzed separately. However, comparison of activity in blasts from AML
and ALL showed a higher level in the former (0.35 v 0.22 nU/mg,
P < .002, n = 17, 35), suggesting that factors other than
genotype may also influence expression.
© 1998 by The American Society of Hematology.
