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Expression of the mdr-1/P-170 gene in patients with acute lymphoblastic
leukemia
ML Rothenberg, LA Mickley, DE Cole, FM Balis, T Tsuruo, DG Poplack and AT Fojo
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
Increased expression of the multidrug resistance gene (mdr-1/P-170) and the
dihydrofolate reductase (DHFR) gene have been implicated in the development
of in vitro drug resistance. Overexpression, with or without gene
amplification, is seen in the development of drug resistance in culture and
it has been postulated that genetic modulation of mdr-1/P-170 and DHFR may
also be involved in the development of clinical drug resistance. We
screened lymphoblasts from 28 patients with acute lymphoblastic leukemia
(ALL) for evidence of overexpression of mdr-1/P-170 using RNAse protection,
RNA in situ hybridization and immunohistochemistry. Overexpression of
mdr-1/P-170 without gene amplification was detected in samples from four
patients (three after multiple relapses, one at presentation).
Overexpression of mdr-1/P-170 was heterogeneous within the population of
malignant lymphoblasts as demonstrated by RNA in situ hybridization,
immunohistochemistry, and drug uptake using daunomycin autofluorescence
analysis. There was no evidence of overexpression of DHFR in any of the
eight patient samples tested by RNAse protection nor was there any evidence
of gene amplification in 11 patient samples on Southern blot analysis. From
these observations it appears that overexpression without gene
amplification of mdr-1/P-170 may be one mechanism of clinical drug
resistance in ALL.
Volume 74,
Issue 4,
pp. 1388-1395,
09/01/1989
Copyright © 1989 by The American Society of Hematology
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