Expression of the mdr-1/P-170 Gene in Patients With Acute Lymphoblastic Leukemia

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...

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Bibliographic Details
Published in:Blood 1989-09, Vol.74 (4), p.1388-1395
Main Authors: Rothenberg, Mace L., Mickley, Lyn A., Cole, Diane E., Balis, Frank M., Tsuruo, Takashi, Poplack, David G., Fojo, Antonio T.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Antineoplastic Agents - therapeutic use
Child
Child, Preschool
Drug Resistance - genetics
Gene Amplification
Genes
Humans
Membrane Glycoproteins - genetics
Molecular Weight
Phenotype
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Recurrence
RNA Probes
RNA, Neoplasm - isolation & purification
Tetrahydrofolate Dehydrogenase - genetics
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V74.4.1388.1388