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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3605-3611
NEOPLASIA
MDR1 gene-related clonal selection and P-glycoprotein
function and expression in relapsed or refractory acute
myeloid leukemia
Marry M. van den Heuvel-Eibrink,
Erik A. C. Wiemer,
Marjan J. de Boevere,
Bronno van der
Holt,
Paula J. M. Vossebeld,
Rob Pieters, and
Pieter Sonneveld
From the Department of Hematology, University
Hospital; the Department of Pediatric Oncology/Hematology, Sophia
Children's Hospital; the Department of Statistics, Daniel den
Hoed Cancer Centre, Erasmus University, Rotterdam; and The
Dutch Childhood Leukemia Study Group, The Hague, The
Netherlands.
The expression of P-glycoprotein (P-gp), encoded by the
MDR1 gene, is an independent adverse prognostic factor for
response and survival in de novo acute myeloid leukemia (AML). Little
is known about MDR1 expression during the development of
disease. The present study investigated whether MDR1 gene-
related clonal selection occurs in the development from diagnosis to
relapsed AML, using a genetic polymorphism of the MDR1 gene
at position 2677. Expression and function of P-gp were studied using
monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was
found in the levels of P-gp function and expression between diagnosis
and relapse in purified paired blast samples from 30 patients with AML.
Thirteen patients were homozygous for the genetic polymorphism of
MDR1 (n = 7 for guanine, n = 6 for thymidine), whereas
17 patients were heterozygous (GT). In the heterozygous patients, no
selective loss of one allele was observed at relapse. Homozygosity for
the MDR1 gene (GG or TT) was associated with shorter
relapse-free intervals (P = .002) and poor survival rates
(P = .02), compared with heterozygous patients. No
difference was found in P-gp expression or function in patients with
AML with either of the allelic variants of the MDR1 gene.
It was concluded that P-gp function or expression is not
upregulated at relapse/refractory disease and expression of one of
the allelic variants is not associated with altered P-gp expression or
function in AML, consistent with the fact that MDR1
gene-related clonal selection does not occur when AML evolves to
recurrent disease.
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